PROCESS FOR PRODUCTION OF 1-(3- (2- (1-BENZOTHIOPHEN-5-YL)-ETHOXY)PROPYL)AZETIDIN-3-OL OR SALTS THEREOF

Abstract

A process for production of 3-(2-(1-benzothiophen-5-yl) ethoxy)propionic acid or salts thereof characterized by subjecting 2- (1-benzothiophen-5-yl)ethanol to Michael addition reaction with acrylonitrile in the presence of base, subsequently subjecting it to reaction with an alcohol represented by the general formula: R1CH2OH wherein R1 represents a hydrogen atom or an unsubstituted or substituted alkyl, cycloalkyl or aryl group, in the presence of acid to obtain a propionic acid ester derivative represented by the general formula: wherein R1 has the same meanings as the above, subsequently subjecting the propionic acid ester derivative to hydrolysis reaction in the presence of base.

Full Text

DESCRIPTION
PROCESS FOR PRODUCTION OF 1-(3-(2-(1-
BENZOTHIOPHEN-5-YL)ETHOXY)PROPYL)
AZETIDIN-3-OL OR SALTS THEREOF
FIELD OF THE INVENTION
[0001]
The present invention relates to a new
process for production of 1-(3-(2-(1-benzothiophen-5-
yl)ethoxy)propyl)azetidin-3-ol or salts thereof which
is useful as remedies for central nervous system and
peripheral nerve diseases.
BACKGROUND ART
[0002]
1-(3-(2-(1-benzothiophen-5-
yl)ethoxy)propyl)azetidin-3-ol or salts thereof has
nerve protective action, nerve regeneration promotion
action and neurite outgrowth action, and is a useful
compound as remedies for central nervous system and
peripheral nerve diseases.
As processes for production of this compound,
for example, (1) a process of reacting 5-(2-(3-
chloropropoxy)ethyl)-1-benzothiophene with 3-azetidinol
or salts thereof, (2) a process of subjecting 1-(3-(2-
(1-benzothiophen-5-yl)ethoxy) propionyl)azetidin-3-ol
obtained from 3-(2-(1-benzothiophen-5-

yl)ethoxy)propionic acid or its salts thereof to
reduction reaction with borane-tetrahydrofuran complex
or subjecting it to reduction reaction with sodium
borohydride in the presence of boron trifluoride
complex tetrahydrofuran complex, and so forth are known
(patent document 1).
However, the process of (1) has the following
defects, (A) the yield is low, (B) complicated
procedures of purification such as silica gel column
chromatography are necessary, (C) therefore, a lot of
waste is egested, and so forth.
In addition, the process of (2) cannot be
satisfied as an industrial manufacturing process,
because the process has the following defects, (A) the
process uses reagents of borane-tetrahydrofuran complex
and boron trifluoride tetrahydrofuran and so forth,
which are harmful to human body, highly flammable,
highly toxic and having problems of stability, (B)
therefore, attention is necessary to handle and store
it and special equipments are required, and so forth.
[0003]
In addition, as a process for production of
3-(2-(1-benzothiophen-5-yl)ethoxy)propionic acid or
salts thereof used in (2) mentioned above, for example,
the following processes are known, (3) a process of
subjecting 2-(1-benzothiophen-5-yl)ethanol to Michael
addition reaction with tert-butyl acrylate,
subsequently subjecting it to de-tert-butylation, (4) a

process of subjecting 2-(1-benzothiophen-5-yl)ethanol
to Michael addition reaction with acrylonitrile,
subsequently subjecting it to hydrolysis with acid, and
so forth (patent document 1).
However, the processes of (3) and (4) cannot
be satisfied as industrial manufacturing processes,
because these processes have the following defects, the
process of (3): (A) by-products form because of the
occurrence of trans-esterification of acrylic acid, (B)
special equipments and treatments are required because
of the occurrence of a large quantity of combustible
isobutene gas in de-tert-butylation reaction, the
process of (4): the yield of hydrolysis with acid is
low, and so forth.
[0004]
As a process for production of 2-(1-
benzothiophen-5-yl)ethanol used in (3) and (4)
mentioned above, for example, the following processes
are known, (5) a process of subjecting 5-methyl-1-
benzothiophene to bromination with N-bromosuccinimide
and to reaction with cyano compounds to obtain (1-
benzothiophen-5-yl)acetonitrile, subsequently
subjecting it to hydrolysis, subsequently subjecting it
to reduction reaction (non-patent document 1, 2 , 3),
(6) a process of reacting 5-bromo-1-benzothiophene with
magnesium to obtain Grignard reagent, subsequently
subjecting it to reaction with ethylene oxide (patent
document 2), (7) a process of subjecting 5-(1-

benzothiophene)carbaldehyde to Wittig reaction with
methoxymethylene ylide, subsequently subjecting it to
hydrolysis to obtain (1-benzothiophen-5-
yl)acetaldehyde, subsequently subjecting it to
reduction reaction, and so forth (patent document 3).
However, the processes of (5) to (7) cannot
be satisfied as industrial manufacturing processes,
because these processes have the following defects, (A)
intermediates have a stimulatory property, (B) a highly
toxic reagent(cyano compounds) is used, (C) a
carcinogenic reagent(ethylene oxide) is used, (D)
highly ignitable reagents(butyllithium, Grignard
reagent) are used, (E) procedures of the reaction are
complicated, and so forth.
[0005]
On the other hand, as processes for
production of benzothiopheneacetic acid derivative or
salts thereof, for example, the following processes are
known, (8) a process of subjecting the hydroxyl group
of benzothiophenemethanol to halogenation, subsequently
subjecting it to reaction with cyano compounds to
obtain benzothiopheneacetonitrile, subsequently
subjecting it to hydrolysis (non-patent document 3),
(9) a process of subjecting 7-oxo-4,5,6,7-
tetrahydrobenzothiophene produced from 3-bromothiophene
to Reformatsky reaction with ethyl bromoacetate,
subsequently subjecting it to aromatization by
dehydrogenation by use of sulfur, and subjecting it to

hydrolysis, and so forth (non-patent document 4).
However, the processes of (8) and (9) cannot
be satisfied as industrial manufacturing processes,
because these processes have the following defects, (A)
intermediates have a stimulatory property, (B) a highly
toxic reagent(cyano compounds) is used, (C) therefore,
complicated treatments of waste are required, (D) there
are many steps of the process (E) the yield is low, (F)
the reaction temperature is high, (G) procedures of the
reaction are complicated, and so forth.
[0006]
In addition, as a process for production of
5-halogeno-1-benzothiophene derivative, for example,
the following processes are known, (10) a process of
reacting 4-halogenothiophenol with 2-
halogenoacetaldehyde dimethylacetal in the presence of
base to obtain 2-(4-halogenophenylthio)acetaldehyde
dimethylacetal, subsequently subjecting it to
intramolecular ring closure reaction in the presence of
polyphosphoric acid, and so forth (non-patent document
5, patent document 4, patent document 5).
However, the process of (10) cannot be
satisfied as an industrial manufacturing process,
because the process has the following defects, (A)
complicated procedures such as distillation or silica
gel column chromatography and so forth are necessary to
isolated because the production intermediates are oily
substances, (B) treatments of the process are

complicated in ring closure reaction by use of
phosphate compound because complicated by-products
form, (C) complicated procedures such as distillation
or silica gel column chromatography and so forth are
necessary to separate 5-halogeno-1-benzothiophene
derivatives from formed by-products because their
derivatives have low melting points, (D) a large
quantities of liquid waste is formed, which contains
phosphorus compounds that require complicated
procedures for treatment, and so forth.
[0007]
As 4-halogenothiophenol used in (10)
mentioned above, for example, (11) a process of
subjecting thioanisole to halogenation with chlorine or
bromine, subsequently subjecting it to demethylation
with large excess of chlorine (patent document 6), (12)
a process of reacting (4-halogenophenylthio)acetic acid
with sodium sulfide in the presence of sodium hydroxide
(patent document 7), (13) a process of reacting
monohalogenobenzene with sulfur monochloride in the
presence of zinc chloride to obtain dihalogenodiphenyl
polysulfide, subsequently subjecting it to reduction
reaction with hydrochloric acid-zinc (patent document
8), (14) a process of reacting 1,4-dihalogenobenzene
with sodium hydrosulfide in l-methyl-2-pyrrolidone
(patent document 9), and so forth are known.
However, the processes of (11) to (14) cannot
be satisfied as industrial manufacturing processes,

because these processes have the following defects, (A)
the yield is low, (B) isomers form, (C) high reaction
temperature is required, (D) reagents that bear large
environment loads such as chlorine or sulfide are used,
and so forth.
[0008]
Further, as a process for production of a
benzothiophene derivative from a (phenylthio) acetic
acid derivative or salts thereof, for example, the
following processes are known, (15) a process of
subjecting it to intramolecular ring closure reaction
in the presence of Lewis acid, subsequently subjecting
it to reduction reaction, subsequently subjecting it to
dehydration reaction, and so forth (patent document
10) .
However, in this process, the structure of
produced compound is limited.
[0009]
[patent document 1]
International publication No. 03/035,647
pamphlet
[patent document 2]
EP0129478 bulletin
[patent document 3]
International publication No. 99/31,056
pamphlet
[patent document 4]
International publication No. 02/100,850

[non-patent document 4]
Journal of Heterocyclic Chemistry (J.
Heterocyclic Chem.), 1965, Vol. 2, p. 44-48
[non-patent document 5]
Journal of Medicinal Chemistry (J. Med.
Chem.), 2003, Vol. 46, p 2446-2455
DISCLOSURE OF THE INVENTION
PROBLEM TO BE SOLVED BY THE INVENTION
[0010]
A new process for production of 1-(3-(2-(1-
benzothiophen-5-yl)ethoxy)propyl)azetidin-3-ol and
salts thereof, process which has safety to human body,
low environmental loads and a possibility of mass
production, is strongly expected.
MEANS TO SOLVE THE PROBLEM
[0011]
Under the circumstances, the present
inventors have studied zealously and consequently, and
found that in a process for production of 1-(3-(2-(1-
benzothiophen-5-yl)ethoxy)propyl)azetidin-3-ol or salts
thereof from 2-(1-benzothiophen-5-yl)ethanol, a process
for production of 3-(2-(1-benzothiophen-5-
yl)ethoxy)propionic acid or salts thereof characterized
by subjecting 2-(1-benzothiophen-5-yl)ethanol to
Michael addition reaction with acrylonitrile in the
presence of base, subsequently subjecting it to

reaction with an alcohol represented by the general
formula [1]:

wherein R1 represents a hydrogen atom or an
unsubstituted or substituted alkyl, cycloalkyl or aryl
group,
in the presence of acid to obtain a propionic acid
ester derivative represented by the general formula
[2]:

wherein R1 has the same meanings as the above,
subsequently subjecting the propionic acid ester
derivative to hydrolysis reaction in the presence of
base;
the propionic acid ester derivative represented by the
general formula [2]:

wherein R1 has the same meanings as the above,
being important intermediates in the production of 3-
(2-(1-benzothiophen-5-yl)ethoxy)propionic acid or salts
thereof;

a process for production of 1-(3-(2-(1-benzothiophen-5-
yl)ethoxy) propionyl)azetidin-3-ol or salts thereof
characterized by deriving 3-(2-(1-benzothiophen-5-
yl)ethoxy)propionic acid or salts thereof to a reactive
derivative, subsequently reacting the reactive
derivative with 3-azetidinol or salts thereof in the
presence of base, and subsequently crystallizing the
crystals from the reaction mixture;
a process for production of 1-(3-(2-(1-benzothiophen-5-
yl)ethoxy)propyl) azetidin-3-ol or salts thereof
characterized by subjecting 1-(3-(2-(1-benzothiophen-5-
yl)ethoxy)propionyl)azetidin-3-ol to reduction reaction
with an addition of activator in the presence of alkali
metal borohydride; and
a process for production of 1-(3-(2-(1-benzothiophen-5-
yl)ethoxy)propyl)azetidin-3-ol or salts thereof
characterized by subjecting 2-(1-benzothiophen-5-
yl)ethanol to Michael addition reaction with
acrylonitrile in the presence of base, subsequently
subjecting it to reaction with an alcohol represented
by the general formula [1]:

wherein R1 has the same meanings as the above,
in the presence of acid to obtain a propionic acid
ester derivative represented by the general formula
[2]:

wherein R1 has the same meanings as the above,
subsequently subjecting the propionic acid ester
derivatives to hydrolysis reaction in the presence of
base to obtain 3-(2-(1-benzothiophen-5-
yl)ethoxy)propionic acid or salts thereof, subsequently
converting it to a reactive derivative, subsequently
reacting the reactive derivative with 3-azetidinol or
salts thereof in the presence of base to obtain 1-(3-
(2-(1-benzothiophen-5-yl)ethoxy)propionyl)azetidin-3-
ol, subsequently subjecting it to reduction reaction
with an addition of activator in the presence of alkali
metal borohydride.
[0012]
In addition, the present inventors have found
that in the process of 2-(1-benzothiophen-5-yl)ethanol
which is a starting material, a process for production
of a 5-halogeno-1-benzothiophene derivative represented
by the general formula [6]:

wherein X1 has the same meanings as the above,
with a halogenating agent to obtain an acid halide
represented by the general formula [4]:

wherein X2 represents a halogen atom; X1 has the same
meanings as the above,
subsequently subjecting the acid halide to
intramolecular ring closure reaction in the presence of
Lewis acid, subsequently subjecting it to reduction
reaction to obtain a dihydrobenzothiophene derivative
represented by the general formula [5]:

wherein X1 has the same meanings as the above,
and subjecting the dihydrobenzothiophene derivative to
dehydration reaction in the presence of acid catalyst;

the dihydrobenzothiophene derivative represented by the
general formula [5]:

wherein X1 has the same meanings as the above,
being important intermediates in the process for
production of a 5-halogeno-1-benzothiophene derivative
represented by the general formula [6]:

wherein X1 has the same meanings as the above;
the 5-halogeno-1-benzothiophene derivative represented
by the general formula [6]:

wherein X1 has the same meanings as the above,
can be produced at simple procedures with a high purity
by crystallizing and isolating crystals of the
dihydrobenzothiophene derivative represented by the
general formula [5]:

wherein X1 has the same meanings as the above,
subsequently subjecting the crystals to dehydration
reaction;
a process for production of benzothiophene derivative
or salts thereof represented by the general formula
[9] :

wherein R2 and R3 represent identically or differently
an unsubstituted or substituted alkyloxycarbonyl,
cycloalkyloxycarbonyl or aralkyloxycarbonyl group or
cyano group,
characterized by coupling a benzothiophene derivative
represented by the general formula [7]:

wherein X1 has the same meanings as the above,
in the presence of base and palladium catalyst with a
malonic acid derivative or salts thereof represented by
the general formula [8]

wherein R2 and R3 have the same meanings as the above;
a process for production of benzothiopheneacetic acid
derivative or salts thereof represented by the general
formula [10]:

wherein R4 represents a hydrogen atom or unsubstituted
or substituted alkyl, cycloalkyl or aralkyl group,
characterized by reacting a benzothiophene derivative
or salts thereof represented by the general formula [9]

wherein R2 and R3 have the same meanings as the above,
with acid or base, subjecting the benzothiophene
derivative or salts thereof to decarboxylation reaction
if necessary;
the benzothiophene derivative represented by the
general formula [9]:

wherein R2 and R3 have the same meanings as the above,
being important intermediates in the process for
production of benzothiopheneacetic acid derivative or
salts thereof represented by the general formula [10]:

wherein R4 has the same meanings as the above;
a process for production of 2-(1-benzothiophen-5-
yl)ethanol characterized by subjecting a
benzothiopheneacetic acid derivative or salts thereof
represented by the general formula [11]:

wherein R4 has the same meanings as the above,
to hydrolysis reaction if necessary, subsequently
subjecting it to reductive reaction with an addition of
activator in the presence of alkali metal borohydride;
and
a process for production of 2-(1-benzothiophen-5-
yl)ethanol characterized by reacting a

(phenylthio)acetic acid derivative or salts thereof
represented by the general formula [3]:

wherein X1 has the same meanings as the above,
with a halogenating agent to obtain an acid halide
represented by the general formula [4]:

wherein X1 and X2 have the same meanings as the above,
subsequently subjecting the acid halide to
intramolecular ring closure reaction in the presence of
Lewis acid, subsequently subjecting it to reduction
reaction to obtain a dihydrobenzothiophene derivative
represented by the general formula [5]:

wherein X1 has the same meanings as the above,
subsequently subjecting the dihydrobenzothiophene
derivative to dehydration reaction in the presence of

acid catalyst to obtain a 5-halogeno-1-benzothiophene
derivative represented by the general formula [6]:

wherein X1 has the same meanings as the above,
subsequently coupling the 5-halogeno-1-benzothiophene
derivative with a malonic acid derivative or salts
thereof represented by the general formula [8]:

wherein R2 and R3 have the same meanings as the above,
in the presence of base and palladium catalyst to
obtain a benzothiophene derivative or salts thereof
represented by the general formula [12]:

wherein R2 and R3 have the same meanings as the above,
subsequently reacting the benzothiophene derivative or
salts thereof with acid or base, subjecting it to
decarboxylation reaction if necessary, to obtain a

benzothiopheneacetic acid derivative or salts thereof
represented by the general formula [11]:

wherein R4 has the same meanings as the above,
subsequently subjecting, the benzothiopheneacetic acid
derivative or salts thereof to hydrolysis reaction if
necessary, subsequently subjecting it to reduction
reaction with an addition of activator in the presence
of alkali metal borohydride.
[0013]
Further, the present inventors have found
that
a process for production of 1-(3-(2-(1-benzothiophen-5-
yl)ethoxy)propyl)azetidin-3-ol or salts thereof
characterized by reacting a (phenylthio)acetic acid
derivative or salts thereof represented by the general
formula [3]:

wherein X1 has the same meanings as the above,
with a halogenating agent to obtain an acid halide
represented by the general formula [4]:

wherein X1 and X2 have the same meanings as the above,
subsequently subjecting the acid halide to
intramolecular ring closure reaction in the presence of
Lewis acid, subsequently subjecting it to reduction
reaction to obtain a dihydrobenzothiophene derivative
represented by the general formula [5]:

wherein X1 has same the meanings as the above,
subsequently subjecting the dihydrobenzothiophene
derivative to dehydration reaction in the presence of
acid catalyst to obtain a 5-halogeno-1-benzothiophene
derivative represented by the general formula [6]:

wherein X1 has the same meanings as the above,
subsequently coupling the 5-halogeno-1-benzothiophene
derivative with a malonic acid derivative or salts
thereof represented by the general formula [8]:

wherein R2 and R3 have same meanings as the above,
in the presence of base and palladium catalyst to
obtain a benzothiophene derivative or salts thereof
represented by the general formula [12]:

wherein R2 and R3 have the same meanings as the above,
subsequently reacting the benzothiophene derivative or
salts thereof with acid or base, subjecting it to
decarboxylation reaction if necessary, to obtain a
benzothiopheneacetic acid derivative or salts thereof
represented by the general formula [11]:

wherein R4 have the same meanings as the above,
subsequently subjecting the benzothiopheneacetic acid
derivative or salts thereof to hydrolysis reaction if
necessary, subsequently subjecting it to reduction
reaction with addition of activator in the presence

of alkali metal borohydride to obtain 2-(1-
benzothiophen-5-yl)ethanol, subsequently subjecting 2-
(1-benzothiophen-5-yl)ethanol to Michael addition
reaction with acrylonitrile in the presence of base,
subsequently subjecting it to reaction with an alcohol
represented by the general formula [1]:

wherein R1 has the same meanings as the above,
in the presence of acid to obtain a propionic acid
ester derivative represented by the general formula
[2] :

wherein R1 has the same meanings as the above,
subsequently subjecting the propionic acid ester
derivative to hydrolysis reaction in the presence of
base to obtain 3-(2-(1-benzothiophen-5-
yl)ethoxy)propionic acid or salts thereof, subsequently
converting 3-(2-(1-benzothiophen-5-yl)ethoxy)propionic
acid or salts thereof to a reactive derivative,
subsequently reacting the reactive derivative with 3-
azetidinol or salts thereof in the presence of base to
obtain 1-(3-(2-(1-benzothiophen-5-
yl)ethoxy)propionyl)azetidin-3-ol, and subsequently

subjecting 1-(3-(2-(1-benzothiophen-5-
yl)ethoxy)propionyl)azetidin-3-ol to reduction reaction
with an addition of activator in the presence of alkali
metal borohydride, and have completed the present
invention.
EFFECT OF THE INVENTION
[0014]
The process for production of 1-(3-(2-(1-
benzothiophen-5-yl)ethoxy)propyl)-3-azetidinol or salts
thereof of the present invention has the following
characteristics, (1) the yield is high, (2) silica gel
column chromatography is not required, (3) therefore,
the amount of wastes is small, (4) reagents which have
harmfulness and problems of stability are not used, and
so forth, and the process is useful as industrial
manufacturing process.
[0015]
The process for production of 3-(2-(1-
benzothiophen-5-yl)ethoxy)propionic acid or salts
thereof of the present invention has the following
characteristics, (1) by-products are small,
(2)inflammable gases do not occur, (3) the yield is
high, and so forth, and the process is useful as
industrial manufacturing process.
[0016]
The process for production of
benzothiopheneacetic acid derivative or salts thereof

represented by the general formula [10] of the present
invention has the following characteristics, (1)
stimulative intermediates are not used during the
process, (2) highly toxic reagents(cyano compounds) are
not used, (3) complicated treatments of waste are not
required, (4) the number of steps of the process is
few, (5) the yield is high, (6) high reaction
temperature is not required, (7) reaction procedures
are simple, and so forth, and the process is useful as
industrial manufacturing process.
[0017]
The process for production of 5-halogeno-1-
benzothiophene derivatives represented by the general
formula [6] of the present invention has the following
characteristics, (1) by-products are few, (2)
purification can be performed by simple procedure such
as extraction and crystallization, (3) therefore,
complicated refining procedures such as distillation or
silica gel column chromatography are not required, and
so forth, and the process is useful as industrial
manufacturing process.
BEST MODE FOR CARRYING OUT THE INVENTION
[0018]
The present invention is explained below in
detail.
In the present specification, unless
otherwise specified, the term "halogen atom" means

the term "aralkyloxycarbonyl group" means an arC1-
6alkyloxycarbonyl group, for example, benzyloxycarbonyl,
phenethyloxycarbonyl or the like;
the terms "aryl group" means group, for example,
phenyl, naphthyl or the like;
the term "alkenyl group" means a C2-12alkenyl group, for
example, vinyl, propenyl, butenyl, pentenyl, hexenyl,
heptenyl, octenyl or the like, respectively.
[0019]
The alkyl, cycloalkyl and aryl group of R1 may
be substituted with at least one group selected from a
halogen atom, a hydroxyl group, a nitro group, an alkyl
group, a cycloalkyl group, an alkoxy group, an alkenyl
group and an aryl group or the like.
The alkyloxycarbonyl, cycloalkyloxycarbonyl
and aralkyloxycarbonyl group of R2 and R3 may be
substituted with at least one group selected from a
halogen atom-, a hydroxyl group, a nitro group, an alkyl
group, a cycloalkyl group, an alkoxy group, an alkenyl
group and an aryl group or the like.
The alkyl, cycloalkyl and aralkyl group of R4
may be substituted with at least one group selected
from a halogen atom, a hydroxyl group, a nitro group,
an alkyl group, a cycloalkyl group, an alkoxy group, an
alkenyl group and an aryl group or the like.
[0020]
In the present invention, the following
processes are given for preferable manufacturing

processes.
[0021]
For the production of 3-(2-(1-benzothiophen-
5-yl)ethoxy)propionic acid or salts thereof, in the
process for production by subjecting 2-(1-
benzothiophen-5-yl)ethanol to Michael addition reaction
in the presence of base with acrylonitrile,
subsequently reacting it with an alcohol represented by
the general formula [1]:

wherein R1 has the same meanings as the above,
in the presence of acid to obtain a propionic acid
ester derivative represented by the general formula
[2] :

wherein R1 has the same meanings as the above,
and subjecting the propionic acid ester derivative to
hydrolysis reaction in the presence of base, the
process for production in which R1 is a hydrogen atom or
an alkyl group is preferable, the process for
production in which R1 is a hydrogen atom, methyl group,
ethyl group or propyl group is more preferable, and the
process for production in which R1 is a hydrogen atom or

ethyl group is further more preferable.
The process for production in which the acid
used is an inorganic acid is preferable, and the
process for production in which the acid used is
sulfuric acid or hydrogen chloride is more preferable.
In the case that the acid is hydrogen
chloride, the process for production in which R1 is
hydrogen atom is preferable.
In the case that the acid is sulfuric acid,
the process for production in which R1 is ethyl group is
preferable.
[0022]
In the process for production of 1-(3-(2-(1-
benzothiophen-5-yl)ethoxy)propyl)azetidin-3-ol or salts
thereof by subjecting 1-(3-(2-(1-benzothiophen-5-
yl)ethoxy)propionyl)azetidin-3-ol to reduction reaction
with an addition of activator in the presence of alkali
metal borohydride, the process for production in which
the alkali metal borohydride used is sodium borohydride
is preferable.
The process for production in which the
activator used is a protonic acid such as sulfuric acid
and hydrogen chloride and so forth is preferable, and
the process for production in which the activator used
is sulfuric acid is more preferable.
In the case that the activator is sulfuric
acid, the process for production in which the volume of
sulfuric acid used is 0.5-0.6 times mole per mole of

the alkali metal borohydride, the addition of sulfuric
acid at 0 to 30°C for 10 minutes to 6 hours and the
subsequent reaction at 30 to 70°C is preferable.
[0023]
For the production of a dihydrobenzothiophene
derivative represented by the general formula [5]:

wherein X1 has the same meanings as the above,
in the process for production by reacting a
(phenylthio)acetic acid derivative or salts thereof
represented by the general formula [3]:

wherein X1 has the same meanings as the above,
with a halogenating agent to obtain an acid halide
represented by the general formula [4]:

wherein X1 and X2 have the same meanings as the above,
subsequently subjecting the acid halide to

wherein X1 has the same meanings as the above,
to coupling reaction with a malonic acid derivative or
salts thereof represented by the general formula [8a]
in the presence of the palladium catalyst and base:

wherein R3a represents an unsubstituted or substituted
alkyloxycarbonyl, cycloalkyloxycarbonyl or
aralkyloxycarbonyl group; R2 has same meanings as the
above,
is preferable, the process for production in which R2 is
an alkyloxycarbonyl group, an aralkyloxycarbonyl group
or a cyano group; R3a is an alkyloxycarbonyl group or an
aralkyloxycarbonyl group is more preferable, the
process for production in which R2 is a C1-
4alkyloxycarbonyl group, an arC1-4alkyloxycarbonyl group
or a cyano group; R3a is a C1-4alkyloxycarbonyl group or
an arC1-4alkyloxycarbonyl group is further preferable.
The process for production in which X1 is a
chlorine atom, a bromine atom or an iodine atom is
preferable, and the process for production in which X1
is a bromine atom or an iodine atom is further

preferable.
The process for production in which X1 bonds
to 4- or 5-positon of the benzothiophene ring is
preferable, and the process for production in which X1
bonds 5-positon of the benzothiophene ring is further
preferable.
[0027]
In the process for production of a
benzothiopheneacetic acid derivative or salts thereof
represented by the general formula [10]:

wherein R4 has the same meanings as the above,
the process for production by reacting a benzothiophene
derivative or salts thereof represented by the general
formula [9a]:

wherein R2 and R3a have the same meanings as the above,
with acid or base, subjecting it to decarboxylation
reaction if necessary, is preferable, the process for
production in which R2 is an alkyloxycarbonyl group, an
aralkyloxycarbonyl group or a cyano group; R3a is an
alkyloxycarbonyl group or an aralkyloxycarbonyl group

is more preferable, and the process for production in
which R2 is a C1-4alkyloxycarbonyl group, an arC1-
4alkyloxycarbonyl group or a cyano group; R3a is a C1-
4alkyloxycarbonyl group or an arC1-4alkyloxycarbonyl
group is further preferable.
[0028]
The process for production in which the group
represented by the general formula:

wherein R2 and R3a have the same meanings as the above,
bonds to 4- or 5-position of the benzothiophene ring is
preferable, and the process for production in which the
group bonds to 5-positon of the benzothiophene ring is
further preferable.
[0029]
The process for production in which the group
represented by the general formula:

wherein R4 has the same meanings as the above, bonds to
4- or 5-position of the benzothiophene ring is
preferable, and the process for production in which the
group bonds to 5-positon of the benzothiophene ring is
further preferable.

The process for production in which R4 is a
hydrogen atom or an unsubstituted or substituted alkyl,
cycloalkyl or aralkyl group is preferable, the process
for production in which R4 is a hydrogen atom, an alkyl
group or an aralkyl group is preferable, and the
process for production in which R4 is a hydrogen atom, a
C1-4alkyl group or an arC1-4 alkyl group is further
preferable.
[0030]
In the propionic acid ester derivative
represented by the general formula [2]:

wherein R1 has the same meanings as the above,
the following compounds are given for a preferable
compound.
The compound of which R1 is a hydrogen atom or
an alkyl group is preferable, the compound of which R1
is a hydrogen atom, a methyl group, an ethyl group or a
propyl group is more preferable, and the compound of
which R1 is a hydrogen atom or an ethyl group is further
preferable.
[0031]
In a dihydrobenzothiophene derivative
represented by the general formula [5]:

wherein X1 has the same meanings as the above,
the following compounds are given for a preferable
compound.
The compound of which X1 is a chlorine atom, a
bromine atom or an iodine atom is preferable, the
compound of which X1 is a bromine atom or an iodine atom
is more preferable, and the compound of which X1 is a
bromine atom is further preferable.
[0032]
In a benzothiophene derivative or salts
thereof represented by the general formula [9]:

wherein R2 and R3 have the same meanings as the above,
the following compounds are given for a preferable
compound.
The compound of which R2 is an
alkyloxycarbonyl, cycloalkyloxycarbonyl or
aralkyloxycarbonyl group or a cyano group is
preferable, the compound of which R2 is an
alkyloxycarbonyl group, an aralkyloxycarbonyl group or

a cyano group is more preferable, and the compound of
which R2 is a C1-4alkyloxycarbonyl group, an arC1-
4alkyloxycarbonyl group or a cyano group is further
preferable.
The compound of which R3 is an
alkyloxycarbonyl, cycloalkyloxycarbonyl or
aralkyloxycarbonyl group is preferable, the compound of
which R3 is an alkyloxycarbonyl group or an
aralkyloxycarbonyl group is more preferable, and the
compound of which R3 is a C1-4alkyloxycarbonyl group or
arC1-4alkyloxycarbonyl group is further preferable.
[0033]
The compound of which the group represented
by the general formula:

wherein R2 and R3 have the same meanings as the above,
bonds to 4- or 5-position of the benzothiophene ring is
preferable, and, the compound of which the group bonds
to 5-position of the benzothiophene ring is further
preferable.
As the representative compound of the general
formula [9] or salts thereof of the present invention,
for example, the following compounds are given.
In a table, Et represents an ethyl group, tBu
represents a tert-butyl group.

[0034]
[0035]
Next, the process for production of the
present invention is explained.
[0036]
[Production process 1]

wherein X1 and X2 have the same meanings as the above.

[0037]
The compound of the general formula [5] can
be produced by deriving the compound of the general
formula [3] or salts thereof to an acid halide,
subsequently subjecting the acid halide to
intramolecular ring closure reaction in the presence of
Lewis acid, subsequently subjecting it to reduction
reaction.
The compound of the general formula [5] can
be derived to the compound of general formula [6]
easily by subjecting it to dehydration reaction in the
presence of acid catalyst.
[0038]
The compound of the general formula [3] or
salts thereof, for example, can be obtained easily and
with good yield by reacting thiophenol with
chloroacetic acid in the presence of base to obtain
(phenylthio)acetic acid, subsequently subjecting
(phenylthio)acetic acid to halogenating reaction, or
reacting 4-halogenothiophenol with chloroacetic acid in
the presence base.
In addition, the salt of the compound of
general formula [3], if it is usually known for a salt
in acidic group such as carboxyl group, is not
particularly limited, but for example, salts with
alkali metal such as sodium, potassium, cesium and the
like;
salts with alkali earth metal such as calcium,

magnesium and the like;
ammonium salts;
and salts with nitrogen containing organic base such as
trimethylamine, triethylamine, tributylamine, N,N-
diisopropylethylamine, pyridine, N-methylpiperidine, N-
methylmorpholine, diethylamine, dicyclohexylamine and
the like; are given.
[0039]
The present process for production is
explained below in detail.
Intramolecular ring closure reaction:
The compound of the general formula [13] can be
produced by reacting the compound of the general
formula [3] or salts thereof with a halogenating agent
to obtain an acid halide, subsequently subjecting the
acid halide to intramolecular ring closure reaction in
the presence of Lewis acid.
[0040]
This reaction is usually carried out in the
presence of solvent, the solvent used, if it does not
affect an influence on the reaction, is not
particularly limited, for example, aliphatic
halogenated hydrocarbons such as dichloromethane,
chloroform, dichloroethane and the like;
nitro compounds such as nitromethane, nitrobenzene and
the like;
and carbon disulfide and the like; are given, and these
solvents may be used in admixture.

As a preferable solvent, aliphatic
halogenated hydrocarbons is given, and dichloromethane
is more preferable.
The amount of the solvent used is not
particularly limited, but is preferably 1 to 50 times
volume per weight(v/w) of the compound of the general
formula [3] or salts thereof, and is more preferably 3
to 15 times(v/w).
[0041]
As the halogenating agent used in this
reaction, for example, phosphorus oxychloride,
phosphorus oxybromide, phosphorus trichloride,
phosphorous pentachloride, thionyl chloride, thionyl
bromide and oxalyl chloride are given, and thionyl
chloride is preferable.
The amount of the halogenating agent used is
different in the kind of the halogenating agent, but
for example, in the case of thionyl chloride, it may be
equal to or more than 0.5 times mole per mole of the
compound of the general formula [3] or salts thereof,
and is preferably 1 to 2 times mole.
[0042]
As Lewis acid used in this reaction, for
example, aluminum chloride, aluminum bromide, boron
trifluoride, titanium tetrachloride, iron chloride, tin
chloride, mercuric chloride, sulfuric acid and the like
are given, and aluminum chloride is preferable.
The amount of Lewis acid used may be equal to

or more than 1 time mole per mole of the compound of
general formula [3] or salts thereof, and is preferably
1 to 5 times mole.
[0043]
The reaction temperature is not particularly-
limited, but is from -20°C to equal to or less than the
boiling point of solvent, and is preferably 0 to 70°C.
The reaction time is not particularly
limited, but is for 10 minutes to 50 hours, and is
preferably for 30 minutes to 20 hours.
[0044]
The compound of the general formula [13]
obtained in this way can be isolated and purified, but
it is preferable to proceed to the next reaction
without isolation.
[0045]
Reduction reaction:
The compound of the general formula [5] can be produced
by subjecting the compound of the general formula [13]
to reduction reaction. This reaction is usually
carried out in the presence of solvent, the solvent
used, if it does not affect an influence on the
reaction, is not particularly limited, but for example,
aliphatic halogenated hydrocarbons such as
dichloromethane, chloroform, dichloroethane and the
like;
ethers such as tetrahydrofuran, 1,2-dimethoxyethane,
bis(2-methoxyethyl)ether, dioxane and the like;

amides such as N,N-dimethylformamide, N,N-
dimethylacetamide, l-methyl-2-pyrrolidone and the like;
sulfoxides such as dimethyl sulfoxide and the like;
alcohols such as methanol, ethanol, propanol, 2-
propanol, butanol and the like;
nitriles such as acetonitrile and the like;
esters such as methyl acetate, ethyl acetate and the
like;
nitro compounds such as nitromethane, nitrobenzene and
the like;
aromatic hydrocarbons such as benzene, toluene, xylene
and the like;
and water and the like; are given, and these solvents
may be used in admixture.
As a preferable solvent, a mixed solvent of
aliphatic halogenated hydrocarbons and alcohols are
given, a mixed solvent of dichloromethane and methanol
is more preferable.
The amount of the solvent used is not
particularly limited, but preferably 1 to 50 times
volume per weight of the compound of the general
formula [13], and is more preferably 3 to 15
times(v/w).
[0046]
As the reducing agent used in this reaction,
for example, alkali metal such as lithium, sodium,
potassium and the like;
alkali earth metal such as magnesium, calcium and the

like;
metal such as zinc, aluminium, chrome, titanium, iron,
samarium, selenium, sodium hydrosulfite and the like,
and salts of these metals;
metal hydride such as diisobutylaluminium hydride,
trialkylaluminium hydride, stannyl hydride compound,
hydrosilane and the like;
complex compound of borohydride such as sodium
borohydride, lithium borohydride, potassium borohydride
and the like;
complex compound of aluminium hydride such as lithium
aluminum hydride and the like;
and borane and alkyl borane and the like; are given.
As a preferable reducing agent, complex
compound of borohydride is given, and sodium
borohydride is more preferable.
The amount of the reducing agent used is
different in the kind of the reducing agent, but for
example, in the case of the complex compound of
borohydride, it may be equal to or more than 0.25 times
mole per mole of the compound of the general formula
[13], and is preferably 0.25 to 2 times mole.
[0047]
The reaction temperature is not particularly
limited, but is from -20°C to equal to or less than the
boiling point of solvent, and is preferably 0 to 70°C.
The reaction time is not particularly
limited, but is for 10 minutes to 50 hours, and is

preferably for 30 minutes to 20 hours.
[0048]
The compound of the general formula [5]
obtained in this way may be used as it is in the next
reaction without isolation, but it is preferable to
isolate it by crystallizing the crystal.
The process of crystallization from aliphatic
hydrocarbons such as hexane, cyclohexane and the like
is preferable, the process of crystallization from
hexane or cyclohexane is more preferable, and the
process of crystallization from cyclohexane is further
preferable.
[0049]
Dehydration reaction:
The compound of the general formula [6] can be produced
by subjecting the compound of the general formula [5]
to dehydration reaction in the presence of acid
catalyst.
[0050]
This reaction is usually carried out in the
presence of solvent, the solvent used, if it does not
affect an influence on the reaction, is not
particularly limited, but for example, aliphatic
hydrocarbons such as hexane, cyclohexane and the like;
aromatic hydrocarbons such as benzene, toluene, xylene
and the like;
aliphatic halogenated hydrocarbons such as
dichloromethane, chloroform, dichloroethane and the

like;
ethers such as tetrahydrofuran, 1,2-dimethoxyethane,
bis(2-methoxyethyl)ether, dioxane and the like;
amides such as N,N-dimethylformamide, N,N-
dimethylacetamide, l-methyl-2-pyrrolidone and the like;
sulfoxides such as dimethyl sulfoxide and the like;
esters such as methyl acetate, ethyl acetate and the
like;
ketones such as acetone, 2-butanone and the like;
alcohols such as methanol, ethanol, propanol, 2-
propanol, butanol and the like;
nitriles such as acetonitrile and the like;
aliphatic carboxylic acid such as acetic acid,
propionic acid and the like;
and water and the like; are given, and these may be
used in admixture.
As a preferable solvent, ketone is given, and
acetone is more preferable.
The amount of the solvent used is not
particularly limited, but is preferably 1 to 50 times
volume per weight of the compound of the general
formula [5], and is preferably 1 to 10 times(v/w).
[0051]
As the acid catalyst used in this reaction,
for example, Broensted acids such as hydrochloric acid,
sulfuric acid, methanesulfonic acid,
trifluoromethanesulfonic acid, p-toluenesulfonic acid,
dichloroacetic acid and the like;

and Lewis acid such as aluminum chloride, boron
trifluoride, boron trichloride and the like; are given,
and p-toluenesulfonic acid is preferable.
The amount of the acid catalyst used may be
equal to or more than 0.0001 times mole per mole of the
compound of the general formula [5], and is 0.001 to 1
times mole.
[0052]
The reaction temperature is not particularly
limited, but is from -20°C to equal to or less than the
boiling point of solvent, and is preferably 0 to 70°C.
The reaction time is not particularly
limited, but is for 10 minutes to 50 hours, and is
preferably for 30 minutes to 20 hours.
[0053]
[Production process 2]

wherein R2, R3 and X1 have the same meanings as the
above.
[0054]
As the compound of the general formula [8] or
salts thereof, for example, diethyl malonate, di(tert-
butyl) malonate, ethyl cyano acetate, tert-butyl cyano

acetate, malononitrile and the like; are marketed.
[0055]
The compound of the general formula [9] or
salts thereof can be produced by subjecting the
compound of the general formula [7] to coupling
reaction with the compound of the general formula [8]
or salts thereof in the presence of base and palladium
catalyst, in the presence or absence of ligand, in the
presence or absence of reducing agent.
This reaction is usually carried out in the
presence of solvent, the solvent used, if it does not
affect a bad influence on the reaction, is not
particularly limited, but for example, aliphatic
hydrocarbons such as hexane, cyclohexane and the like;
halogenated hydrocarbons such as dichloromethane,
chloroform, dichloroethane and the like;
ethers such as tetrahydrofuran, 1,2-dimethoxyethane,
bis(2-methoxyethyl)ether, dioxane and the like;
aromatic hydrocarbons such as benzene, toluene, xylene
and the like;
amides such as N,N-dimethylformamide, N,N-
dimethylacetamide, l-methyl-2-pyrrolidone and the like;
sulfoxides such as dimethyl sulfoxide and the like;
esters such as ethyl acetate, butyl acetate and the
1 i ke ;
ketones such as acetone, 2-butanone and the like;
alcohols such as methanol, ethanol, propanol, butanol,
2-propanol, 2-methyl-2-propanol and the like;

and nitriles such as acetonitrile and the like; are
given, and these may be used in admixture.
The amount of the solvent used is not
particularly limited, but is preferably 1 to 20 times
volume per weight of the compound of the general
formula [7], and is preferably 1 to 10 times(v/w).
As the base used in this reaction, for
example, metal alkoxide such as sodium methoxide,
sodium ethoxide, potassium tert-butoxide and sodium
tert-butoxide and the like;
inorganic base such as sodium hydroxide, potassium
hydroxide, sodium carbonate, potassium carbonate,
cesium carbonate, barium carbonate, sodium phosphate,
potassium phosphate, sodium hydride and potassium
hydride and the like;
organic base such as triethylamine, N,N-
diisopropylethylamine, pyridine and the like; are
given.
The amount of the base used may be equal to
or more than 1 time mole per mole of the compound of
the general formula [7], is preferably 2 to 10 times
mole, and is more preferably 2 to 4 times mole.
[0056]
As the palladium catalyst used in this
reaction, for example, metal palladium such as
palladium-carbon, palladium black and the like;
inorganic palladium salt such as palladium chloride;
organic palladium salt such as palladium acetate;

organopalladium complex such as
tetrakis(triphenylphosphine) palladium (0),
bis(triphenylphosphine)palladium (II) chloride, 1,1'-
bis(diphenylphosphino)ferrocene palladium (II)
chloride, tris(dibenzylideneacetone)dipalladium (0) and
the like;
and polymer fixed organopalladium complex such as
bis(acetate)triphenylphosphine palladium (II) carried
in polymer, di(acetate)dicyclohexylphosphine palladium
(II) carried in polymer and the like; are given.
The amount of the palladium catalyst used is
not particularly limited, but is preferably 0.0001 to 1
times mole per mole of the compound of general formula
[7], and is more preferably is 0.005 to 0.1 times mole.
[0057]
As the ligand used, if desired, in this
reaction, for example, trialkylphosphines such as
trimethylphosphine, tri(tert-butyl)phosphine and the
like;
tricycloalkylphosphines such as tricyclohexylphosphine
and the like;
triarylphosphines such as triphenylphosphine,
tritolylphosphine and the like;
trialkyl phosphites such as trimethyl phosphite,
triethyl phosphite, tributyl phosphite and the like;
tricycloalkyl phosphites such as tricyclohexyl
phosphite and the like;
triaryl phosphites such as triphenyl phosphite and the

like;
imidazolium salt such as 1,3-bis(2,4,6-
trimethylphenyl)imidazolium chloride and the like;
diketones such as acetylacetone,
octafluoroacetylacetone and the like;
amines such as trimethylamine, triethylamine,
tripropylamine, triisopropylamine and the like;
1,1'-bis(diphenylphosphino)ferrocene;
and 2,2-bis(diphenylphosphino)-1,1'-binaphthyl and the
like; are given.
The amount of the ligand used is not
particularly limited, but is preferably 0.0001 to 2
times mole per mole of the compound of general formula
[7], and is more preferably 0.005 to 0.2 times mole.
[0058]
As the reducing agent used, if desired, in
this reaction, for example, complex compound of
borohydride such as lithium borohydride, sodium
borohydride, calcium borohydride, triacetoxy sodium
borohydride, sodium cyano borohydride and the like; is
given.
The amount of the reducing agent used is not
particularly limited, but is preferably 0.0001 to 1
times mole per mole of the compound of general formula
[7], and is more preferably 0.01 to 0.1 times mole.
The amount of the compound of general formula
[8] is 1 to 5 times mole per mole of the compound of
general formula [7], and is preferably 1 to 2 times

mole.
This reaction may be carried out at 0 to
200°C, and preferably at 50 to 150°C for 1 minute to 24
hours.
[0059]
The compound of general formula [9] or salts
thereof obtained in this way may be used as it is in
the next reaction without isolation.
[0060]
[Production process 3]

wherein R2, R3 and R4 have the same meanings as the
above.
[0061]
The compound of the general formula [10] or
salts thereof can be produced by reacting the compound
of the general formula [9] or salts thereof with acid
or base in the presence or absence of water, in the
presence or absence of alcohol, subjecting it to
decarboxylation reaction if necessary.
This reaction is usually carried out in the
presence of solvent, the solvent used, if it does not
affect a bad influence on the reaction, is not
particularly limited, but for example, aliphatic

hydrocarbons such as hexane, cyclohexane and the like;
halogenated hydrocarbons such as dichloromethane,
chloroform, dichloroethane and the like;
ethers such as tetrahydrofuran, 1,2-dimethoxyethane,
bis(2-methoxyethyl)ether, dioxane and the like;
aromatic hydrocarbons such as benzene, toluene, xylene
and the like;
amides such as N,N-dimethylformamide, N,N-
dimethylacetamide, l-methyl-2-pyrrolidone and the like;
sulfoxides such as dimethyl sulfoxide and the like;
esters such as ethyl acetate, butyl acetate and the
like;
ketones such as acetone, 2-butanone and the like;
alcohols such as methanol, ethanol, propanol, butanol,
2-propanol, 2-methyl-2-propanol and the like;
glycols such as ethylene glycol, propylene glycol,
diethylene glycol and the like;
nitriles such as acetonitrile and the like;
and water and the like; are given, and these may be
used in admixture.
The amount of the solvent used is not
particularly limited, but is preferably 1 to 50 times
volume per weight of the compound of the general
formula [9] or salts thereof, and is more preferably 1
to 15 times(v/w).
[0062]
As the acid used in this reaction, inorganic
acid such as hydrochloric acid, sulfuric acid,

phosphoric acid, hydrogen chloride, hydrogen bromide
and the like;
organic carboxylic acid such as acetic acid,
trichloroacetic acid, trifluoroacetic acid and the
like;
and organic sulfonic acid such as methanesulfonic acid,
p-toluenesulfonic acid and the like; are given.
The amount of the acid used may be equal to
or more than 0.001 times mole per mole of the compound
of the general formula [9] or salts thereof, and is
preferably 0.01 to 5 times mole.
In addition, the acid may be used as solvent.
In addition, as the base used in this
reaction, for example, metal alkoxide such as sodium
methoxide, sodium ethoxide, potassium tert-butoxide and
sodium tert-butoxide and the like;
inorganic base such as sodium hydroxide, potassium
hydroxide, barium hydroxide, sodium carbonate,
potassium carbonate and the like;
and organic base such as triethylamine, N,N-
diisopropylethylamine, pyridine and the like; are
given.
The amount of base used is 2 to 10 times mole
per mole of the compound of general formula [9] or
salts thereof, and is preferably 2 to 5 times mole.
The amount of water used, if desired, in this
reaction, is not particularly limited, but is
preferably 0.5 to 5 times volume per weight of the

compound of general formula [9] or salts thereof in
order to make it have the function of solvent.
As the alcohol used, if desired, in this
reaction, for example, primary alcohols such as
methanol, ethanol, propanol, butanol and the like;
and glycols such as ethylene glycol, propylene glycol,
diethylene glycol and the like; are given.
The amount of the alcohol used is not
particularly limited, but is preferably 0.5 to 5 times
volume per weight of the compound of general formula
[9] or salts thereof in order to make it have the
function of solvent.
This reaction may be carried out at 0 to
200°C, and preferably at 20 to 150°C for 1 minute to 24
hours.
[0063]
Decarboxylation reaction which may be
performed if necessary is carried out by heating
As the acid used, if desired, in this reaction, for
example, inorganic acid such as hydrochloric acid,
sulfuric acid, phosphoric acid, hydrogen chloride,
hydrogen bromide and the like;
organic carboxylic acid such as acetic acid,
trichloroacetic acid, trifluoroacetic acid and the
like;
and organic sulfonic acid such as methanesulfonic acid,
p-toluene sulfonic acid and the like; are given.
The amount of the acid used may be equal to

or more than 0.001 times mole per mole of the compound
of general formula [9] or salts thereof, and is
preferably 0.01 to 5 times mole.
In addition, the acid may be used as solvent.
[0064]
This reaction may be carried out if necessary
in coexistent of solvent.
The solvent used, if it does not affect a bad
influence on the reaction, is not particularly limited,
but for example, aliphatic hydrocarbons such as hexane,
cyclohexane and the like;
halogenated hydrocarbon such as dichloromethane,
chloroform, dichloroethane and the like;
ethers such as tetrahydrofuran, 1,2-dimethoxyethane,
bis(2-methoxyethyl)ether, dioxane and the like;
aromatic hydrocarbons such as benzene, toluene, xylene
and the like;
amides such as N,N-dimethylformamide, N,N-
dimethylacetamide, l-methyl-2-pyrrolidone and the like;
sulfoxides such as dimethyl sulfoxide and the like;
esters such as ethyl acetate, butyl acetate and the
like;
ketones such as acetone, 2-butanone and the like;
alcohols such as methanol, ethanol, propanol, butanol,
2-propanol, 2-methyl-2-propanol and the like;
glycols such as ethylene glycol, propylene glycol,
diethylene glycol and the like;
nitriles such as acetonitrile and the like;

and water and the like; are given, and these may be
used in admixture.
This reaction may be carried out at 50 to
200°C, and preferably at 50 to 150°C for 1 minute to 24
hours.
[0065]
[Production process 4]

wherein R4 has the same meanings as the above.
[0066]
2-(1-benzothiophen-5-yl)ethanol of the
compound of the formula [15] can be produced by
subjecting the compound of the general formula [11] or
salts thereof to hydrolysis reaction if necessary, and
deriving it to (1-benzothiophen-5-yl)acetic acid or
salts thereof of the compound of the formula [14],
subsequently subjecting (1-benzothiophen-5-yl)acetic
acid or salts thereof to reduction reaction with an
addition of activator in the presence of alkali metal
borohydride.
This reaction is usually carried out in the
presence of solvent, the solvent used, if it does not
affect an influence on the reaction, is not
particularly limited, but for example, ethers such as
tetrahydrofuran, 1,2-dimethoxyethane, bis(2-

methoxyethyl)ether, dioxane and the like; is given, and
tetrahydrofuran is preferable.
In addition, these solvents may be mixed with
a solvent of halogenated hydrocarbons such as
dichloromethane, chloroform and the like;
aromatic hydrocarbons such as benzene, toluene, xylene
and the like;
and aliphatic hydrocarbons such as hexane, cyclohexane,
octane and the like; and the mixed solvent may be used.
The amount of the solvent used is not
particularly limited, but is preferably 1 to 20 times
volume per weight of the compound of the formula [14]
or salts thereof, and is preferably 2 to 10 times(v/w).
[0067]
As the alkali metal borohydride used in this
reaction, for example, sodium borohydride, lithium
borohydride, potassium borohydride and the like; are
given, and sodium borohydride is preferable.
The amount of the alkali metal borohydride
used may be equal to or more than 1 time mole per mole
of the compound of the formula [14] or salts thereof,
is preferably 1 to 10 times mole, and is more
preferably 1 to 2 times mole.
[0068]
As the activator used in this reaction, for
example, protonic acid such as sulfuric acid, hydrogen
chloride, trifluoroacetic acid and the like is given,
and sulfuric acid and hydrogen chloride are preferable.

The amount of the activator used is different
in the kind of the activator, but for example, but in
the case of sulfuric acid it is preferably 0.5 to 1
times mole per mole of the alkali metal borohydride,
and is more preferably 0.5 to 0.6 times mole.
In addition, the addition time of the
activator is different in the kind of the activator,
but in the case of sulfuric acid it is preferably for
10 minutes to 6 hours, and is more preferably for 30
minutes to 2 hours.
In addition, the activator may be dissolved
in solvent appropriately, and the dissolved solvent may
be added.
[0069]
The reaction temperature is not particularly
limited, but may be -20 to 150°C, and is preferably 0 to
80°C.
Further, the process by the addition of the
activator at 0 to 30°C and the subsequent reaction at 40
to 80°C is more preferable, because generation of by-
products can be suppressed.
In addition, the reaction time is not
particularly limited, but is for 10 minutes to 50
hours, and is preferably for 1 to 20 hours.
[0070]
In addition, the hydrolysis reaction of the
compound of the general formula [11] or salts thereof
which may be carried out if necessary may be performed

by a reaction in a manner per se, for example, the
compound of the formula [14] or salts thereof can be
derived by subjecting it to hydrolysis reaction in the
presence of base.
This reaction is usually carried out in the
presence solvent, the solvent used, if it does not
affect an influence on the reaction, is not
particularly limited, but for example, aliphatic
hydrocarbons such as hexane, cyclohexane and the like;
aromatic hydrocarbons such as benzene, toluene, xylene
and the like;
halogenated hydrocarbons such as dichloromethane,
chloroform and the like;
ethers such as tetrahydrofuran, 1,2-dimethoxyethane,
bis(2-methoxyethyl)ether, dioxane and the like;
sulfoxides such as dimethyl sulfoxide and the like;
alcohols such as methanol, ethanol, propanol, butanol,
2-propanol, tert-butanol and the like;
and water and the like; are given, and these solvents
may be used in admixture.
As a preferable solvent, a mixed solvent of
aromatic hydrocarbons such as benzene, toluene and
xylene and alcohols, and a mixed solvent of alcohols
and water; are given, and a mixed solvent of toluene
and methanol and a mixed solvent of methanol and water
are preferable.
The amount of the solvent used is not particularly
limited, but is preferably 0.5 to 10 times volume per

weight of the compound of the general formula [11] or
salts thereof, and is more preferably 0.5 to 5
times(v/w).
As the base used in this reaction, for
example, metal alkoxide such as sodium methoxide,
sodium ethoxide, potassium tert-butoxide, sodium tert-
butoxide and the like;
and inorganic base such as sodium hydroxide, potassium
hydroxide, barium hydroxide, sodium carbonate,
potassium carbonate and the like; are given.
As a preferable base, inorganic base is
given, and sodium hydroxide and potassium hydroxide are
preferable.
The amount of base used may be equal to or
more than 1 time mole per mole of the compound of the
general formula [11] or salts thereof, and is
preferably 1 to 3 times mole.
This reaction is preferably performed by an
addition of water.
The amount of water added may be equal to or
more than 1 time mole per mole of the compound of the
general formula [11] or salts thereof, is preferably
0.1 to 10 times(v/w), and is more preferably 0.3 to 2
times(v/w) in order to make it have the function of
solvent.
The reaction temperature is not particularly
limited, but it may be from 0°C to equal to or less than
the boiling point of solvent, and is preferably 10 to

4 0°C.
The reaction time is not particularly
limited, but may be for 10 minutes to 50 hours, and is
preferably for 1 to 24 hours.
[0071]
The compound of the formula [14] or salts
thereof obtained in this way can be isolated from the
reaction mixture after the termination of the reaction
in the usual manner.
For example, after the termination of the
reaction, it can be isolated by acidification with a
diluted hydrochloric acid, extraction with organic
solvent such as toluene, and subsequent removal of
solvent.
In addition, it can be isolated as a salt by
the way of an addition of base into the extract.
As the salt of the compound of the formula
[14], the salt, if it is usually known for a salt in
acidic group such as carboxyl group, is not
particularly limited, but for examples, salts with
alkali metal such as sodium, potassium, cesium and the
like;
salts with alkali earth metal such as calcium,
magnesium and the like;
ammonium salts,
and salts with nitrogen containing organic base such as
trimethyl amine, triethylamine, tributylamine, N,N-
diisopropylethylamine, pyridine, N-methylpiperidine, N-

methylmorpholine, diethylamide, dicyclohexylamine and
the like; are given.
As a preferable salt, a salt with alkali metal such as
sodium and potassium is given, and a sodium salt is
preferable.
[0072]
[Production process 5]

wherein R1 has the same meanings as the above.
[0073]
3-(2-(1-benzothiophen-5-yl)ethoxy)propionic
acid of the compound of the formula [17] or salts
thereof can be produced by subjecting the compound of
the formula [15] to Michael addition reaction with
acrylonitrile in the presence of base to obtain the
compound of the formula [16], subsequently subjecting
the compound of the formula [16] to reaction with the
alcohol of the general formula [1] in the presence of
acid, subsequently deriving it to the compound of
general formula [2], and subjecting the compound of
general formula [2] to hydrolysis reaction in the
presence of base.
[0074]

The present process for production is
explained below in detail.
Michael addition reaction:
The compound of the formula [16] can be produced by
subjecting the compound of the formula [15] to Michael
addition reaction with acrylonitrile in the presence of
base.
This reaction is usually carried out in the
presence of solvent, the solvent used, if it does not
affect an influence on the reaction, is not
particularly limited, but for example, aliphatic
hydrocarbons such as hexane, cyclohexane and the like;
aromatic hydrocarbons such as benzene, toluene, xylene
and the like;
halogenated hydrocarbons such as dichloromethane,
chloroform and the like;
ethers such as tetrahydrofuran, 1,2-dimethoxyethane,
bis(2-methoxyethyl)ether, dioxane and the like;
sulfoxides such as dimethyl sulfoxide and the like;
and tertiary alcohols such as tert-butanol, tert-amyl
alcohol and the like; are given, and these may be used
in admixture.
As a preferable solvent, a sole solvent of
aromatic hydrocarbons and a mixed solvent of aromatic
hydrocarbons, ethers and tertiary alcohols are given, a
sole solvent of aromatic hydrocarbons, a mixed solvent
of aromatic hydrocarbons and ethers, and a mixed
solvent of aromatic hydrocarbons and tertiary alcohols

are preferable, toluene, a mixed solvent of toluene and
tetrahydrofuran, a mixed solvent of toluene and tert-
butanol, and a mixed solvent of toluene and tert-amyl
alcohol are more preferable.
The amount of the solvent used is not
particularly limited, but is preferably 0.5 to 10 times
volume per weight of the compound of the formula [15],
and is more preferably 0.5 to 3 times(v/w).
In addition, as an additive to these
solvents, primary alcohols such as small amount of
methanol and ethanol and the like;
secondary alcohols such as 2-propanol and the like;
and water and the like; these may be mixed.
The amount of the additive used is equal to
or less than 0.5 times volume per weight of the
compound of the formula [15], and is preferably equal
to or less than 0.1 times(v/w).
[0075]
As the base used in this reaction, for
example, organic base such as 1,8-
diazabicyclo[5.4.0]undec-7-ene(DBU),
tetramethylammonium hydroxide, benzyltrimethylammonium
hydroxide and the like;
metal alkoxide such as sodium methoxide, sodium
ethoxide, potassium tert-butoxide, sodium tert-butoxide
and the like;
inorganic base such as sodium hydroxide, potassium
hydroxide, sodium hydride and the like; are given.

As a preferable base, organic base and metal
alkoxide are given, benzyltrimethylammonium hydroxide
and potassium tert-butoxide are more preferable.
The amount of the base used may be equal to
or more than 0.0001 times mole per mole of the compound
of the formula [15], and is preferably 0.01 to 0.1
times mole.
[0076]
In addition, this reaction may be carried out
in the presence of catalyst.
As the catalyst used, if desired, quaternary ammonium
salt which is usually known is given,
tetrabutylammonium bromide, benzyltrimethylammonium
chloride and benzyltrimethylammonium bromide are
preferable.
The amount of the catalyst used may be equal
to or more than 0.0001 times mole per mole of the
compound of the formula [15], and is preferably 0.01 to
0.1 times mole.
As the base, for example, in the case that
inorganic base such as sodium hydroxide and potassium
hydroxide and the like are used, it is preferable to
perform this reaction in the presence of catalyst.
The amount of acrylonitrile used in this
reaction may be equal to or more than 1 time mole per
mole of the compound of the formula [15], and is
preferably 1 to 2 times mole.
The reaction temperature is not particularly

limited, but may be from 0°C to equal to or less than
the boiling point of solvent, and is preferably 0 to
35°C.
The reaction time is not particularly
limited, but may be for 1 minute to 24 hours, and is
preferably for 30 minutes to 4 hours.
The compound of the formula [16] obtained in
this way may be used as it is in the next reaction
without isolation.
[0077]
Esterification reaction:
The compound of the general formula [2] can be produced
by subjecting the compound of formula [16] to reaction
with the alcohol of the general formula [1] in the
presence acid.
As the acid used in this reaction, for
example, inorganic acid such as hydrochloric acid,
sulfuric acid, hydrogen chloride, hydrogen bromide and
the like;
and organic sulfonic acid such as methanesulfonic acid,
p-toluenesulfonic acid and the like; are given.
As a preferable acid, inorganic acid is
given, and sulfuric acid and hydrogen chloride are more
preferable.
The amount of the acid used is different in
the amount of the solvent used, but may be equal to or
more than 1 time mole per mole of the compound of the
formula [16], and is preferably 2 to 10 times mole.

As the alcohol of general formula [1] used in
this reaction, a straight chain alkyl alcohols such as
methanol, ethanol, propanol, butanol, pentanol and the
like;
branched chain alkyl alcohols such as isobutanol and
the like;
substituted alkyl alcohols such as methoxy ethanol,
chloroethanol, cyclohexanethanol and the like;
and aralkyl alcohols such as benzyl alcohol, phenethyl
alcohol and the like; are given.
As a preferable alcohol, straight chain alkyl
alcohols are given, and methanol, ethanol, propanol and
butanol are more preferable.
The amount of the alcohol used may be equal
to or more than 1 time mole pre mole of the compound of
the formula [16], is preferable 0.5 to 10 times(v/w),
and is more preferably 0.5 to 5 times(v/w) in order to
make it have the function of solvent.
[0078]
In this reaction, in the case that inorganic
acid such as sulfuric acid and hydrogen chloride and
the like;
and organic sulfonic acid such as methanesulfonic acid
and the like; are used, it is preferable to perform the
reaction with an addition of water.
The amount of water added may be equal to or
more than 1 time mole per mole of the compound of the
formula [16], is preferably 1 to 10 times mole, and is

more preferably 1 to 6 times mole.
This reaction may be performed in the
presence of solvent.
As the solvent used, it is not particularly
limited, but the same as Michael addition reaction is
given.
The reaction temperature is not particularly
limited, but may be from 0°C to equal to or less than
the boiling point of solvent, and is preferably 20 to
150°C.
The reaction time is not particularly
limited, but may be for 10 minutes to 50 hours, and is
preferably for 1 to 24 hours.
The compound of the general formula [2]
obtained in this way may be used as it is to the next
reaction without isolation.
[0079]
Hydrolysis reaction:
The compound of the general formula [17] or salts
thereof can be produced by hydrolyzing the compound of
formula [2] in the presence of base.
This reaction is usually carried out in the
presence of solvent, the solvent used, if it does not
affect an influence on the reaction, is not
particularly limited, but for example, aliphatic
hydrocarbons such as hexane, cyclohexane and the like;
aromatic hydrocarbons such as benzene, toluene, xylene
and the like;

halogenated hydrocarbons such as dichloromethane,
chloroform and the like;
ethers such as tetrahydrofuran, 1,2-dimethoxyethane,
dioxane and the like;
sulfoxides such as dimethyl sulfoxide and the like;
alcohols such as methanol, ethanol, propanol, butanol,
2-propanol, tert-butanol and the like;
and water and the like; are given, and these solvents
may be used in admixture.
As a preferable solvent, a mixed solvent of the solvent
used in the esterification reaction and alcohols, and a
mixed solvent of alcohols water are given, and a mixed
solvent of toluene and methanol, and a mixed solvent of
methanol and water are more preferable.
The amount of the solvent used is not
particularly limited, but is preferably 0.5 to 10 times
volume per weight of the compound of the general
formula [2], and is more preferably 0.5 to 3
times(v/w).
As the base used in this reaction, for
example, metal alkoxide such as sodium methoxide,
sodium ethoxide, potassium tert-butoxide, sodium tert-
butoxide and the like;
and inorganic base such as sodium hydroxide, potassium
hydroxide, barium hydroxide, sodium carbonate,
potassium carbonate and the like; are given.
As a preferable base, inorganic base is
given, and sodium hydroxide and potassium hydroxide are

preferable.
The amount of the base used may be equal to
or more than 1 time mole per mole of the compound of
the general formula [2], and is preferably 1 to 3 times
mole.
This reaction is preferably performed with an
addition of water.
The amount of water added may be equal to or
more than 1 time mole per mole of the compound of the
general formula [2], is preferably 0.1 to 10
times(v/w), and is more preferably 0.3 to 2 times(v/w)
in order to make it have the function of solvent.
The reaction temperature is not particularly
limited, but may be from 0°C to equal to or less than
the boiling point of solvent, and is preferably 10 to
4 0°C.
The reaction time is not particularly
limited, but may be for 10 minutes to 50 hours, and is
preferably 1 to 24 hours.
[0080]
The compound of the formula [17] or salts
thereof obtained in this way can be isolated from the
reaction mixture after the termination of the reaction
in the usual manner.
For example, after the termination of the
reaction, it can be isolated by acidification with
diluted hydrochloric acid, subsequent extraction with
organic solvent such as toluene and removal of solvent.

In addition, it can be isolated as a salt by
an addition of base into the extract.
As the salt of the compound of the formula
[17], the salt, if it is usually known for a salt in
acidic group such as carboxyl group, is not
particularly limited, but for example, salts with
alkali metal such as sodium, potassium, cesium and the
like;
salts with alkali earth metal such as calcium,
magnesium and the like;
ammonium salt,
and salts with nitrogen containing organic base such as
trimethyl amine, triethylamine, tributylamine, N,N-
diisopropylethylamine, pyridine, N-methylpiperidine, N-
methylmorpholine, diethylamine, dicyclohexylamine and
the like; are given.
As a preferable salt, a salt with alkali
metal such as sodium and potassium and the like is
given, and a sodium salt is more preferable.
[0081]
[Production processes 6]

1-(3-(2-(1-benzothiophen-5-

yl)ethoxy)propionyl)azetidin-3-ol of the compound of
the formula [18] can be produced by deriving the
compound of the formula [17] or salts thereof to a
reactive derivative, subsequently subjecting the
reactive derivative to amidation reaction with 3-
azetidinol or salts thereof in the presence of base.
[0082]
The present process for production is
explained below in detail.
[0083]
Derivation to reactive derivative:
The compound of formula [17] or salts thereof can be
derived to a reactive derivative by reacting it with an
activator.
As the reactive derivative, for example, an
acid halide, an acid anhydride, an activated amide and
an activated ester and the like; are given, and an acid
halide is preferable.
As the process of deriving it to the reactive
derivative, for example, the derivation to the acid
halide with the use of a halogenating agent such as
thionyl chloride, oxalyl chloride, phosphorus
trichloride, phosphorous pentachloride and the like;
the derivation to the acid anhydride by condensation
with an acid halide such as ethyl chloroformate,
isobutyl chloroformate, pivaloyl chloride and the like;
the derivation to the activated amide by use of
imidazole condensation and an activated amidation agent

such as carbonyldiimidazole and the like;
and the derivation to the activated ester by-
condensation with p-nitrophenol, 2-
mercaptobenzothiazole and the like; are given.
As the derivation to the reactive derivative,
the derivation to the acid halide by use of a
halogenating agent is preferable, and the derivation to
the acid chloride by use of thionyl chloride is more
preferable.
The amount of the activator used in this
derivation is different in the kind of the activator,
but for example, in the case of thionyl chloride, it
may be equal to or more than 0.5 times mole per mole of
the compound of the formula [17] or salts thereof, and
is preferably 1 to 2 times mole.
This reaction is usually carried out in the
presence of solvent, the solvent used, if it does not
affect an influence on the reaction, is not
particularly limited, but for example, aliphatic
hydrocarbons such as hexane, cyclohexane and the like;
aromatic hydrocarbons such as benzene, toluene, xylene
and the like;
halogenated hydrocarbons such as dichloromethane,
chloroform and the like;
ethers such as tetrahydrofuran, 1,2-dimethoxyethane,
bis(2-methoxyethyl)ether, dioxane and the like;
amides such as N,N-dimethylformamide, N,N-
dimethylacetamide, l-methyl-2-pyrrolidone and the like;

sulfoxides such as dimethyl sulfoxide and the like;
esters such as methyl acetate, ethyl acetate and the
like;
ketones such as acetone, 2-butanone and the like;
and nitriles such as acetonitrile and the like; are
given, and these may be used in admixture.
As a preferable solvent, aromatic
hydrocarbons such as benzene, toluene and xylene and
the like and ethers such as tetrahydrofuran, 1,2-
dimethoxyethane, bis(2-methoxyethyl)ether, dioxane and
the like are given, and toluene and 1,2-dimethoxyethane
are preferable.
The amount of the solvent used is not
particularly limited, but is preferably 1 to 20 times
volume per weight of the compound of the formula [17]
or salts thereof, and is more preferably 1 to 10
times(v/w).
The reaction temperature is not particularly
limited, but is preferably -60 to 150°C, and is more
preferably -30 to 120°C.
The reaction time is not particularly
limited, but is for 10 minutes to 50 hours, and is
preferably 30 minutes to 20 hours.
The reactive derivative of the compound of
the formula [17] or salts thereof derived in this way
can be isolated and purified, but it is preferable to
proceed to the next reaction without isolation.
[0084]

Amidation reaction:
The compound of the formula [18] can be produced by
reacting the solution of the reactive derivative of the
compound of the formula [17] or salts thereof described
above with 3-azetidinol or salts thereof in the
presence of base.
As the base used in this reaction, for
example, organic base such as triethylamine,
diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-
ene(DBU), pyridine and the like;
and inorganic base such as sodium hydroxide, potassium
hydroxide, sodium carbonate, potassium carbonate,
sodium hydrogen carbonate, potassium hydrogencarbonate
and the like; are given.
As a preferable base, inorganic base is
given, and sodium hydroxide is more preferably.
The amount of the base used may be equal to
or more than 1 time mole per mole of the compound of
the formula [17] or salts thereof, and is preferably 1
to 10 times mole.
The amount of 3-azetidinol or salts thereof
may be equal to or more than 1 time mole per mole of
the compound of the formula [17] or salts thereof, and
is preferably 1 to 2 times mole.
In addition, it is preferable to use 3-
azetidinol or salts thereof in aqueous solution.
The amount of water having 3-azetidinol or
salts thereof dissolved is not particularly limited,

but is preferably 1 to 20 times volume per weight of
the compound of the formula [17] or salts thereof, and
is preferably 1 to 10 times(v/w).
The reaction temperature is not particularly
limited, but is preferably -60 to 100°C, and is more
preferably -30 to 50°C.
The reaction time is not particularly
limited, but is for 10 minutes to 50 hours, and is
preferably for 30 minutes to 20 hours.
After the termination of the reaction, the
compound of the formula [18] obtained in this way can
be isolated and purified by crystallization from the
reaction mixture by performing treatments such as
neutralization of the reaction mixture and dilution
with water if necessary, and subsequent operation of
warming and cooling.
[0085]
[Production process 7]

1-(3-(2-(1-benzothiophen-5-yl)ethoxy)propyl)azetidin-3-
ol of the compound of the formula [19] or salts thereof
can be produced by subjecting the compound of the
formula [18] to reduction reaction with an addition of
activator such as a protonic acid, a methylating agent
and a silylating agent and the like in the presence of

alkali metal borohydride.
This reaction is usually carried out in the
presence of solvent, the solvent used, if it does not
affect an influence on the reaction, is not
particularly limited, but for example, ethers such as
tetrahydrofuran, 1,2-dimethoxyethane, bis(2-
methoxyethyl)ether, dioxane and the like; is given, and
tetrahydrofuran is more preferable.
In addition, these solvents may be used in
admixture of halogenated hydrocarbons such as
dichloromethane, chloroform and the like;
aromatic hydrocarbons such as benzene, toluene, xylene
and the like;
and aliphatic hydrocarbons such as hexane, cyclohexane,
octane and the like.
The amount of the solvent used is preferably
1 to 20 times volume per weight of the compound of the
formula [18], and is more preferably 3 to 10
times(v/w).
[0086]
As the alkali metal borohydride used in this
reaction, for example, sodium borohydride, lithium
borohydride, potassium borohydride and the like; are
given, and sodium borohydride is preferable.
The amount of the alkali metal borohydride is
preferably 1 to 10 times mole per mole of the compound
of the formula [18], and is more preferably 2 to 3
times mole.

[0087]
As the activator used in this reaction, for
example, protonic acid such as sulfuric acid, hydrogen
chloride, trifluoroacetic acid and the like;
methylating agent such as dimethyl sulfate and the
like;
and silylating agent such as trimethylsilyl chloride
and the like; are given.
As a preferable activator, protonic acid such
as sulfuric acid , hydrogen chloride and the like; is
given, and sulfuric acid is more preferable.
The amount of the activator used is different
in the kind of the activator, but for example, in the
case of sulfuric acid, it is preferably 0.5 to 1 times
mole per mole of alkali metal borohydride, and is more
preferably 0.5 to 0.6 times mole.
In addition, the addition time of the
activator is different in the kind of the activator,
but in the case of sulfuric acid, it is preferably for
10 minutes to 6 hours, and is more preferably for 30
minutes to 4 hours.
In addition, the activator may be dissolved
in solvent appropriately, and the dissolved solvent may
be added.
[0088]
Further, in the case that the amount of the
alkali metal borohydride is 2.0 to 2.2 times mole per
mole of the compound of the formula [18] and the amount

of sulfuric acid is 0.5 to 0.6 times mole per mole of
the alkali metal borohydride and the dropping time of
the sulfuric acid is 1 to 4 hours, the compound of the
formula [19] or salts thereof having high purity can be
obtained because of the further suppression of the
formation of by-products
[0089]
The reaction temperature is not particularly
limited, but may be -20 to 150°C, and is preferably 0 to
70°C.
After an addition of activator at 0 to 30°C,
it is preferable to react at 30 to 70°C, and after an
addition of activator at 0 to 30°C, it is more
preferable to react at 40 to 60°C.
The reaction time is not particularly
limited, but may be for 10 minutes to 50 hours, is
preferably for 1 to 20 hours.
[0090]
In the present invention, as a preferable
process for production, the following process is given,
the process by suspending the compound of the
formula [18] in ether (3-10 times(v/w)), adding alkali
metal borohydride(2 to 3 times mole), adding activator
at 0 to 30°C, and subsequently reacting at 30 to 70°C
for 1 to 20 hours is preferable, the process by
suspending the compound of the formula [18] in ether (3
to 10 times(v/w)), adding sodium borohydride (2 to 3
times mole), adding protonic acid (0.5 to 1 times mole

per mole of sodium borohydride) at 0 to 30°C, and
subsequently reacting at 30 to 70°C for 1 to 20 hours is
more preferable, and the process by suspending the
compound of formula [18] in tetrahydrofuran (3 to 10
times(v/w)), adding sodium borohydride (2.0 to 2.2
times mole), adding sulfuric acid (0.5 to 0.6 times
mole per mole of sodium borohydride), adding sulfuric
acid at 0 to 30°C for 1 to 4 hours, and subsequently
reacting at 40 to 60°C for 1 to 20 hours is further
preferable.
[0091]
After the termination of the reaction, the
compound of the formula [19] or salts thereof obtained
in this way can be isolate in usual manner.
For example, after the termination of the
reaction, it can be isolated by adding 6.0mol/L
hydrochloric acid to decompose an excessive reducing
agent, cooling to room temperature, subsequently making
the reaction mixture alkaline with aqueous sodium
hydroxide, extracting with organic solvent such as
ethyl acetate, and subsequently removing the solvent
from the extract.
In addition, it can be isolated as a salt by
an addition of acid into the extract.
[0092]
As the salt of the compound of the formula
[19], the salt, if it is usually known for a salt in
basic group such as amino group, is not particularly

limited, but for example, salts with mineral acid such
as hydrochloric acid, hydrobromic acid, nitric acid,
sulfuric acid and the like;
salts with organic carboxylic acid such as formic acid,
acetic acid, citric acid, oxalic acid, fumaric acid,
maleic acid, succinic acid, malic acid, tartaric acid,
aspartic acid, trichloroacetic acid, trifluoroacetic
acid and the like;
and salts with sulfonic acid such as methanesulfonic
acid, benzenesulfonic acid, toluenesulfonic acid,
mesitylene sulfonic acid, naphthalenesulfonic acid and
the like; are given.
As a preferable salt, a pharmacologically
acceptable salt is given, and a salt with maleic acid
is more preferable.
[0093]
In the compound of the present invention, if
isomer (for example, optical isomer), hydrate, solvate
and various kinds of crystalline forms exist, the
present invention includes these all.
In addition, in the compound used by the
process for production described above, if isomer (for
example, optical isomer), hydrate, solvate and various
kinds of crystal form exist, all these can be used in
the process for production of the present invention.
Examples
[0094]

Next, the present invention will be described
in the following reference examples and examples.
However, the present invention is not intended to be
limited thereto.
The mixing ratios in the eluents are by volume. A case
without description in particular, the carrier in
silica gel column chromatography is B.W. silica gel,
BW-127ZH or PSQ100B(product of Fuji Silysia Chemical
Ltd.).
The abbreviations in examples mean the following:
Me: methyl, Et: ethyl, Pr: propyl, Bu: butyl, tBu: tert-
butyl DMSO-d6: dimethylsulfoxide-d6
[0095]
Reference Example 1

To water(275mL) suspension of 546g of
thiophenol was dropwise added water(550mL) solution of
585g of potassium hydroxide at no more than 20°C. Next,
thereto was dropwise added a water(825mL) solution of
492g of chloroacetic acid, which was then stirred at 80
to 90°C for 3 hours. After cooling the reaction
mixture, the pH was adjusted to 1.5 with hydrochloric
acid, and thereto were added 1650mL of dichloromethane
and 550mL of water. The organic layer was separated,
and anhydrous magnesium sulfate was added. Insoluble

matter was filtered off, and to the filtrate was added
5.95g of iron(III) chloride, and dropwise added 832g of
Bromine at 5 to 10°C, which was then stirred at room
temperature for 5 hours. After cooling the reaction
solution to 5°C, thereto was dropwise added water(825mL)
solution of 187g of sodium sulfite, and the pH was
adjusted 1.2 with hydrochloric acid. After stirring at
5 to 10°C for 1 hour, the precipitate was collected by
filtration to provide solid matter. To this solid
matter was added 2000mL of toluene, from which water
was removed by heating and azeotropic distillation.
The reaction mixture was cooled to 5°C over a period of
2 hours. After stirring at the same temperature for 1
hour, crystals precipitate was collected by filtration
to provide 1108g of (4-bromophenylthio)acetic acid as
white solid form.
1H-NMR (CDCl3) δ value: 3.65(2H,s),7.25-7.35(2H,m),7.40-
7.50(lH,m)
[0096]
Reference Example 2

To water(600mL) solution of 88.9g of sodium
hydroxide was added 200g of 4-bromothiophenol and
dropwise added water(300mL) solution of 105g of
chloroacetic acid, which was then stirred at 60 to 70°C

for 1 hour. After cooling the reaction mixture to 40°C,
thereto were added 140mL of hydrochloric acid and 600mL
of toluene, which was t

hen heated to 80°C. The organic
layer was separated and slowly cooled to 5°C. After
stirring at the same temperature for 1 hour, the
crystals precipitate was collected by filtration to
provide 243g of (4-bromophenylthio)acetic acid as white
solid form.
The Chemical shift values of 1H-NMR spectral
in CDCl3 agreed with the values of reference example 1.
[0097]
Example 1-1

To dichloromethane(7 50mL) suspension of 250g
of (4-bromophenylthio)acetic acid were added 2.5mL of
N, N-dimethylformamide and 132g of thionyl chloride,
which was then refluxed for 1 hour. After cooling the
reaction mixture to 20°C, thereto was dropwise added
dichloromethane(1500mL) suspension of 148g of aluminum
chloride at 5 to 15°C, which was then stirred at 15 to
25°C for 1.5 hours. Next, this reaction mixture was
added dropwise to a mixed solution of 1310mL of water
and 188mL of hydrochloric acid under cooling. The
organic layer was separated, thereto was added 1250mL
of water, and the pH was adjusted to 3.0 with 5%

potassium carbonate aqueous solution. The organic
layer was separated and cooled to 5°C. Thereto were
added 15.3g of sodium borohydride and 500mL of
methanol, which was then stirred at 10 to 20°C for 2
hours. To the reaction solution was added 750mL of
water, followed by adjustment to pH7.0 using acetic
acid and left unattended in room temperature overnight.
To the reaction solution was added 200mL of 5%
potassium hydroxide aqueous solution, and the organic
layer was separated. To the organic layer was 25.0g of
activated carbon, which was then stirred at room
temperature. Insoluble matter was filtered off, and
the solvent of filtrate was distilled off. To the
resultant residue was added cyclohexane, the crystals
precipitated were collected by filtration to provide
194g of 5-bromo-2,3-dihydro-1-benzothiophen-3-ol as
pale red solid form.
1H-NMR (CDCl3) δ value:
2.18(lH,d,J=8.3Hz),3.30(1H,dd,J=12.0,4.4Hz),3.61(lH,dd,
J=12.0,6.3Hz),5.30-5.40(lH,m),7.11(1H,d,J=8.3Hz),
7.35(1H,dd,J=8.3,2.0Hz),7.50(1H,d,J=2.0Hz)
[0098]
Example 1-2

To acetone(600mL) solution of 300g of 5-
bromo-2,3-dihydro-1-benzothiophen-3-ol was added 12.4g
of p-toluenesulfonic acid monohydrate, which was then
refluxed for 2 hours. To the reaction solution was
added 15.0g of activated carbon, which was then
stirred. Insoluble matter was filtered off and washed
with 300mL of acetone. The filtrate and washings were
combined, to which was dropwise added 2700mL of water
at 5 to 15°C. The precipitate was collected by
filtration to provide 268g of 5-bromo-1-benzothiophene
as pale purple solid form.
1H-NMR (CDCl3) δ value:
7.27(lH,d,J=5.4Hz),7.44(1H,dd,J=8.5,1.9Hz),7.48(1H,d,J=
5.4Hz),7.74(lH,d,J=8.5Hz),7.97(1H,d,J=l.9Hz)
[0099]
Example 2-1

(1) To 1,2-dimethoxyethane(10mL) suspension of
0.02g of tris(dibenzylideneacetone)dipalladium(0) were
added O.llg of 10%(w/w)tri(tert-butyl)phosphine/hexane,
1.76g of cesium carbonate, 0.50g of 5-
bromobenzothiophene and 0.45g of diethyl malonate,
which was then refluxed for 2 hours. To the reaction
mixture were added water and ethyl acetate, followed by
adjustment to pH2 using 2mol/L hydrochloric acid. The

organic layer was separated, and dried over anhydrous
magnesium sulfate, followed by distilling off the
solvent under reduced pressure. The resultant residue
was purified using silica gel column chromatography
(eluent; hexane:ethyl acetate = 10:1) to provide 0.69 g
of diethyl 2-(1-benzothiophen-5-yl)malonate as white
solid form.
1H-NMR (CDCl3) δ value:
1.27(6H,t,J=7.1Hz),4.1-4.3(4H,m),4.73(lH,s),7.33
(lH,d, J=5.4Hz),7.40(lH,dd,J=8.3,2.0Hz),7.45(1H,d,J=5.4H
z),7.87(lH,d,J=8.3Hz),7.87(1H,d,J=2.0Hz)
(2) To ethylene glycol(1.0mL) suspension of 0.25g
of diethyl 2-(1-benzothiophen-5-yl)malonate were added
1.0mL of 40%(w/w) potassium hydroxide aqueous solution
and 0.3mL of water, which was then refluxed for 2
hours. To the reaction mixture were added water and
toluene, and the aqueous layer was separated. The pH
was adjusted to 2 with 6mol/L hydrochloric acid, and
thereto was added ethyl acetate. The organic layer was
separated, and dried over anhydrous magnesium sulfate,
followed by distilling off the solvent under reduced
pressure. The resultant residue was suspended to 5mL
of xylene, and thereto was added 0.01g of p-
toluenesulfonic acid monohydrate, which was then
refluxed for 30 minutes. The solvent was distilled off
under reduced pressure, and to the resultant residue
were added toluene and cyclohexane. The precipitate
was collected by filtration to provide 0.02g of 2-(1-

(1) To 1, 2-dimethoxyethane(lOmL) solution of
O.llg of 10%(w/w)tri(tert-butyl)phosphine/hexane were
added 0.02g of
tris(dibenzylideneacetone)dipalladium(O), 1.76g of
cesium carbonate, 0.50g of 5-bromobenzothiophene and
0.61g of tert-butyl malonate, which was then refluxed
for 2 hours. Next, thereto were added 0.02g of
tris(dibenzylideneacetone)dipalladium(0) and O.llg of
10%(w/w)tri(tert-butyl)phosphine/hexane, which was then
refluxed for 1 hour. This reaction mixture was added
to a mixed solution of 30mL of water and 20mL of ethyl
acetate, and the pH was adjusted to 3 with 6mol/L
hydrochloric acid. The organic layer was separated,

and dried over anhydrous magnesium sulfate, followed by
distilling off the solvent under reduced pressure. The
resultant residue was purified using silica gel column
chromatography (eluent; hexane: ethyl acetate = 20:1)
to provide 0.49 g of di (tert-butyl) 2-(1-benzothiophen-
5-yl)malonate as white solid form.
1H-NMR (CDCl3) δ value:
1.47(18H,s),4.55(lH,s),7.32(1H,d,J=5.4Hz),7.39(1H,dd,J=
8.5,1.7Hz),7.43(lH,d,J=5.4Hz),7.84(1H,d,J=l.7Hz) ,7.86(1
H,d,J=8.5Hz)
(2) To toluene(2.5mL) solution of 0.25g of
di(tert-butyl) 2-(1-benzothiophen-5-yl)malonate was
added 0.01g of p-toluenesulfonic acid monohydrate,
which was then refluxed for 1 hour. After cooling the
reaction mixture, the precipitate was collected by
filtration to provide 0.14g of 2-(1-benzothiophen-5-
yl)malonic acid as white solid form.
1H-NMR (CDCl3) δ value:
4.80(lH,s),7.3-7.5(lH,m),7.47(1H,d,J=5.5Hz),
7.77(lH,d,J=5.5Hz),7.89(lH,s),7.97(1H,d,J=8.3Hz)
(3) To xylene(2mL) suspension of 0.10g of 2-(1-
benzothiophen-5-yl)malonic acid was added 4mg of p-
toluenesulfonic acid monohydrate, which was then
refluxed for 1 hour. The solvent was distilled off
under reduced pressure, and to the resultant residue
was added cyclohexane. The precipitate was collected
by filtration to provide 0.08g of 2-(1-benzothiophen-5-
yl)acetic acid as white solid form.

The Chemical shift values of 1H-NMR spectral
in CDCl3 agreed with the values of example 2-1(2).
[0101]
Example 2-3

To toluene(3mL) solution of 0.21g of ethyl
cyanoacetate were added 0.41g of potassium tert-
butoxide, 0.30g of 5-bromobenzothiophene and 0.02g of
tetrakis(triphenylphosphine)palladium(0), which was
then refluxed for 7.5 hours. To the reaction mixture
was added water, and the pH was adjusted to 2 with
hydrochloric acid. Thereto was added ethyl acetate,
and insoluble matter was filtered off. The organic
layer was separated, washed with water, and dried over
anhydrous magnesium sulfate, followed by distilling off
the solvent under reduced pressure. The resultant
residue was purified using silica gel column
chromatography (eluent; hexane:ethyl acetate =5:1) to
provide 0.16g of ethyl 2-(1-benzothiophen-5-yl)-2-
cyanoacetate as pale yellow solid form.
1H-NMR (CDCl3) δ value:
1.29(3H,t, J=7.1Hz),4.25(2H,m),4.84(lH,s),7.37(1H,d,J=5.
4Hz),7.41(lH,dd,J=8.5,1.7Hz),7.54(1H,d,J=5.4Hz),7.92(1H
,d,J=8.5Hz),7.94(lH,d,J=1.7Hz)

[0102]
Example 2-4

To toluene(25mL) suspension of 0.16g of
dichlorobis(triphenylphosphine)palladium(II) were added
0.12g of triphenylphosphine, 0.01g of sodium
borohydride, 5.7 9g of potassium tert-butoxide and 2.92g
of ethyl cyanoacetate, which was then stirred at room
temperature for 10 minutes. Thereto were added 5.00g
of 5-bromobenzothiophene and 25mL of toluene, which was
then refluxed for 4 hours. Thereto was added 0.14g of
tetrakis(triphenylphosphine)palladium(0), which was
then refluxed for 2 hours. Next, to the reaction
solution were added 25mL of ethanol, 2.82g of sodium
hydroxide and 5mL of water, which was then refluxed for
6 hours. Thereto was added 2.82g of sodium hydroxide,
which was then refluxed for 5 hours. To the reaction
mixture were added 15mL of water and 0.5g of activated
carbon, and insoluble matter was filtered off. The
aqueous layer was separated, and to the solution was
added 35mL of ethanol. The pH was adjusted to 2 with
15mL of hydrochloric acid. Thereto was added 15mL of
water, which was then stirred at 40°C. Thereto was
added 30mL of water, which was stirred. After that, it
was cooled. The precipitate was collected by

[0104]
Example 2-6

To 1,2-dimethoxyethane(1.00L) solution of
250g of 5-bromobenzothiophene were added 276g of
potassium tert-butoxide and 174g of tert-butyl
cyanoacetate. Thereto were added 8.23g of
dichlorobis(triphenylphosphine)palladium(II) and 6.15g
of triphenylphosphine at 80 to 85°C, which was then
refluxed for 2 hours. Next, to the reaction mixture
were added 500mL of ethylene glycol, 250mL of water and
263g of potassium hydroxide, which was then refluxed
for 4 hours. To the reaction mixture were added 1.50L
of water and 12.5g of kieselguhr (cellpure, product of
Advanced Minerals Company). After insoluble matter was
filtered off, to the filtrate was added 250mL of
toluene, and the aqueous layer was separated. To the
aqueous layer were added 375mL of toluene and 375mL of
ethyl acetate, the pH was adjusted to 1 with 505mL of
hydrochloric acid, and the organic layer was separated.
The organic layer was treated with 12.5g of activated
carbon. The solvent was distilled off under reduced
pressure, to which was added toluene. The precipitate
was collected by filtration to provide 176g of 2-(1-
benzothiophen-5-yl)acetic acid as white solid form.

The Chemical shift values of 1H-NMR spectral
in CDCl3 agreed with the values of example 2-1(2).
[0105]
Example 2-7

To 1,2-dimethoxyethane(3mL) solution of 0.30g
of 4-bromobenzothiophene were added 0.33g of potassium
tert-butoxide, 0.21g of tert-butyl cyanoacetate, 0.01g
of dichlorobis(triphenylphosphine)palladium(II) and
0.01g of triphenylphosphine, which was then refluxed
for 40 minutes. Thereto were added 0.33g of potassium
tert-butoxide, 0.01g of dichlorobis(triphenylphosphine)
palladium(II) and 0.01g of triphenylphosphine, which
was then refluxed for 30 minutes. The reaction mixture
was added to a mixed solution of water and ethyl
acetate, and the pH was adjusted to 1 with 6mol/L
hydrochloric acid. The organic layer was separated,
and dried over anhydrous magnesium sulfate, followed by
distilling off the solvent under reduced pressure. The
resultant residue was purified using silica gel column
chromatography (eluent; hexane:ethyl acetate = 5:1) to
provide 0.26g of tert-butyl 2-(1-benzothiophen-4-yl)-2-
cyanoacetate as pale brown oily form.
1H-NMR(CDCl3) δ value:

1.42(9H,s),5.03(lH,s),7.39(1H,t,J=7.8Hz),7.49(lH,d,J=7.
8Hz),7.54(lH,d,J=5.6Hz),7.59(1H,d,J=5.6Hz),7.92(lH,d,J=
7.8Hz)
(2) To ethylene glycol(1.0mL) solution of 0.25g
of tert-butyl 2-(1-benzothiophen-4-yl)-2-cyanoacetate
were added 1.0mL of aqueous solution of
40%(w/w)potassium hydroxide and 0.3mL of water, which
was then stirred at 95 to 105°C for 1 hour. To the
reaction mixture were added water and toluene, and the
aqueous layer was separated. The pH was adjusted to 2
with 6mol/L hydrochloric acid, to which was added ethyl
acetate. The organic layer was separated, and dried
over anhydrous magnesium sulfate, followed by
distilling off the solvent under reduced pressure. To
the resultant residue was added cyclohexane. The
precipitate was collected by filtration to provide
0.15g of 2-(1-benzothiophen-4-yl)acetic acid as white
solid form.
1H-NMR(CDCl3) δ value:
3.95(2H,s),7.2-7.4(2H,m),7.41(1H,d,J=5.5Hz),
7.47(lH,d,J=5.5Hz),7.82(1H,d,J=7.8Hz)
[0106]
Example 3-1

To 340mL of tetrahydrofuran was suspended

50.2g of sodium borohydride, to which were dropped
tetrahydrofuran(340mL) solution of 170g of (1-
benzothiophen-5-yl)acetic acid, and 65.1g of sulfuric
acid successively, which was then stirred at room
temperature for 2.5 hours. To this reaction mixture
was dropwise added 85mL of acetone, which was then
stirred for 30 minutes. Thereto were added 510mL of
water and 680mL of toluene. The organic layer was
separated, to which was added 510mL of water, and the
pH was adjusted to 12 with 48mL of 20%(w/w)sodium
hydroxide aqueous solution. The organic layer was
separated, and washed with water, followed by
distilling off the solvent. Thereto were added
cyclohexane and toluene. The precipitate was collected
by filtration to provide 135g of 2-(1-benzothiophen-5-
yl)ethanol as white solid form.
1H-NMR(CDCl3) δ value:
1.41(lH,t,J=6.0Hz),2.99(2H,t,J=6.5Hz),3.8-4.0(2H,m),
7.22(lH,dd,J=8.3,1.7Hz),7.30(1H,d,J=5.4Hz),7.44(1H,d,J=
5.4Hz),7.6-7.7(lH,m),7.83(1H,d,J=8.3Hz)
[0107]
Example 3-2
To 5mL of 1,2-dimethoxyethane was suspended
2.95g of sodium borohydride, to which were dropwise
added 1,2-dimethoxyethane(25mL) solution of 10g of (1-
benzothiophen-5-yl)acetic acid, and 11mL of 6.9mol/L
hydrochloride/1,2-dimethoxyethane solution, which was
then stirred at room temperature for 1 hour. To this

reaction mixture was dropwise added 5mL of acetone,
which was then stirred for 30 minutes. Thereto were
added 20mL of water, 30mL of toluene and 2mL of 2mol/L
hydrochloric acid. Next, after the pH was adjusted to
9.5 with 20mL of 2mol/L sodium hydroxide aqueous
solution, the organic layer was separated. The organic
layer was dried over anhydrous magnesium sulfate,
followed by distilling off the solvent. Thereto were
added cyclohexane and toluene. The precipitate was
collected by filtration to provide 7.84g of 2-(1-
benzothiophen-5-yl)ethanol as white solid form.
[0108]
Example 3-3
To 40mL of tetrahydrofuran was suspended
4.72g of sodium borohydride, to this solution were
dropwise added tetrahydrofuran(60mL) solution of 20g of
(1-benzothiophen-5-yl)acetic acid, and 6.12g of
sulfuric acid. The solution was heated to 66°C,
followed by distilling off about 4 0mL of the solvent
under normal pressure, which was then stirred at same
temperature for 1 hour. After cooling, to this
reaction mixture was dropwise added 10mL of acetone,
which was then stirred for 30 minutes. Thereto were
added 90mL of water and 80mL of toluene. The organic
layer was separated, to which was added 60mL of water,
and the pH was adjusted to 13.6 with 5mL of 5mol/L
sodium hydroxide aqueous solution. The organic layer
was separated, washed with water, followed by

distilling off the solvent, and thereto were added
cyclohexane and toluene. The precipitate was collected
by filtration to provide 16.5g of 2-(1-benzothiophen-5-
yl)ethanol as white solid form.
The Chemical shift values of 1H-NMR spectral
in CDCl3 agreed with the values of example 3-1.
[0109]
Example 4-1

(1) To toluene(5mL) suspension of 0.23g of
40%(w/w)benzyltrimethylammonium hydroxide aqueous
solution was added 5.00g of 2-(1-benzothiophen-5-
yl)ethanol, and dropwise added 2.20mL of acrylonitrile
at 0 to 5°C, which was then stirred at 0 to 20°C for 1
hour. To this reaction mixture was added 0.125mL of
hydrochloric acid. Thereto were added 10mL of
propanol, 1.0mL of water and 3.lmL of sulfuric acid,
which was then refluxed for 6.5 hours. After cooling,
to the reaction mixture were added 10mL of water and
10mL of toluene. The organic layer was separated, and
dried over anhydrous magnesium sulfate. After
insoluble matter was filtered off, the solvent was
distilled off under reduced pressure. The resultant
residue was purified using silica gel column

chromatography (eluent; hexane:ethyl acetate = 15:1 to
7:1) to provide 7.21g of propyl 3-(2-(1-benzothiophen-
5-yl)ethoxy)propionate as colorless oily form.
1H-NMR(CDCl3) δ value:
0.91(3H,t,J=7.4Hz),1.57-1.67(2H,m),2.58(2H,t,J=6.4Hz),
2.99(2H,t,J=7.1Hz),3.71(2H,t,J=7.1Hz),3.74(2H,t,J=6.4Hz
),4.02(2H,t,J=6.7Hz),7.20(1H,dd,J=8.2,1.6Hz),7.28(lH,d,
J=5.6Hz),7.41(lH,d,J=5.6Hz),7.60-7.70(lH,m),7.78
(lH,d,J=8.2Hz)
(2) To methanol(12mL) solution of 12.Og of propyl
3-(2-(1-benzothiophen-5-yl)ethoxy)propionate was added
water(12mL) solution of 2.76g of potassium hydroxide,
which was then stirred at room temperature for 1.5
hours. This reaction mixture was distilled off under
reduced pressure, to which were added 36mL of toluene
and 36mL of water. The pH was adjusted to 1.9 with 8mL
of 6mol/L hydrochloric acid. The organic layer was
separated, followed by distilling off the solvent under
reduced pressure. Thereto were added 12mL of toluene
and 24mL of cyclohexane. The precipitate was collected
by filtration to provide 8.91g of 3-(2-(1-
benzothiophen-5-yl)ethoxy)propionic acid as white solid
form.
1H-NMR(CDCl3) δ value:
2.63(2H,t,J=6.2Hz),3.00(2H,t,J=7.1Hz),3.72(2H,t,J=7.1Hz
),3.74(2H,t,J=6.2Hz),7.20(1H,dd,J=8.4,1.6Hz),7.27(lH,dd
,J=5.5,0.6Hz),7.40(lH,d,J=5.5Hz),7.65-7.70(lH,m),7.78
(lH,d,J=8.4Hz)

[0110]
Example 4-2

(1) To toluene(5mL) suspension of 5.00g of 2-(1-
benzothiophen-5-yl)ethanol were added 0.23g of
40%(w/w)benzyltrimethylammonium hydroxide aqueous
solution and 2.28mL of tetrahydrofuran, and dropwise
added 2.20mL of acrylonitrile at 0 to 10°C, which was
then stirred at same temperature for 1.5 hours. To
this reaction mixture were added 0.1mL of hydrochloric
acid, 10mL of butanol and 5mL of 50%(w/w) sulfuric
acid, which was then refluxed for 15 hours. After
cooling, to the reaction mixture was added 15mL of
water. The organic layer was separated, and dried over
anhydrous magnesium sulfate. After insoluble matter
was filtered off, the solvent was distilled off under
reduced pressure. The resultant residue was purified
using silica gel column chromatography(eluent;
hexane:ethyl acetate =10:1) to provide 6.65g of butyl
3-(2-(1-benzothiophen-5-yl)ethoxy)propionate as
colorless oily form.
1H-NMR(CDCl3) δ value:
0.92(3H,t,J=7.4Hz),1.30-1.45(2H,m),1.50-1.65(2H,m),2.57
(2H,t,J=6.3Hz),2.99(2H,t,J=7.1Hz),3.71(2H,t,J=7.1Hz),3.

7 4(2H,t,J=6.3Hz),4.0 6(2H,t,J=6.7Hz),7.21(lH,dd,J=8.3,1.
7Hz),7.28(lH,dd,J=5.4,0.7Hz),7.41(1H,d,J=5.4Hz),7.65-
7.7 0(lH,m),7.78(1H,d,J=8.3Hz)
(2) To methanol(5mL) solution of 5.00g of butyl
3-(2-(1-benzothiophen-5-yl)ethoxy)propionate was added
water(5mL) solution of 1.10g of potassium hydroxide,
which was then stirred at room temperature for 2 hours.
This reaction mixture was distilled off under reduced
pressure, to which were added 30mL of toluene and 30mL
of water. The pH was adjusted to 1.6 with 3.5mL of
6mol/L hydrochloric acid. The organic layer was
separated, followed by distilling off the solvent under
reduced pressure. Thereto were added 15mL of toluene
and 30mL of cyclohexane. The precipitate was collected
by filtration to provide 3.60g of 3-(2-(1-
benzothiophen-5-yl)ethoxy)propionic acid as white solid
form.
The Chemical shift values of 1H-NMR spectral
in CDCl3 agreed with the values of example 4-1(2).
[0111]
Example 4-3

(1) To toluene(5mL) suspension of 5.00g of 2-(1-
benzothiophen-5-yl)ethanol were added 0.23g of

40%(w/w)benzyltrimethylammonium hydroxide aqueous
solution and 2.28mL of tetrahydrofuran, and dropwise
added 2.22mL of acrylonitrile at 5°C, which was then
stirred at 0 to 15°C for 1.5 hours. To this reaction
mixture were added 0.13mL of hydrochloric acid, 10mL of
methanol and 1.52g of water. Thereto was introduced
9.47g of hydrogen chloride, which was then refluxed for
4 hours. After cooling, to the reaction mixture were
added 15mL of water and 10mL of toluene. The organic
layer was separated, and dried over anhydrous magnesium
sulfate. After insoluble matter was filtered off, the
solvent was distilled off under reduced pressure. The
resultant residue was purified using silica gel column
chromatography(eluent; hexane:ethyl acetate =5:1) to
provide 7.36g of methyl 3-(2-(1-benzothiophen-5-
yl)ethoxy)propionate as colorless oily form.
1H-NMR(CDCl3) δ value:
2.58(2H,t,J=6.4Hz),2.99(2H,t,J=7.1Hz),3.65(3H,s),3.71(2
H,t,J=7.1Hz),3.74(2H,t,J=6.4Hz),7.20(1H,dd,J=8.3,1.7Hz)
,7.28(lH,d,J=5.4Hz),7.41(1H,d,J=5.4Hz),7.65-7.70(lH,m),
7.78(lH,d,J=8.3Hz)
(2) To methanol(5mL) solution of 5.00g of methyl
3-(2-(1-benzothiophen-5-yl)ethoxy)propionate was added
water(5mL) solution of 1.27g of potassium hydroxide,
which was then stirred at room temperature for 2 hours.
This reaction mixture was distilled off under reduced
pressure, to which were added 30mL of toluene and 30mL
of water. The pH was adjusted to 1.0 with 5mL of

6mol/L hydrochloric acid. The organic layer was
separated, followed by distilling off the solvent under
reduced pressure. Thereto were added 11mL of toluene
and 30mL of cyclohexane. The precipitate was collected
by filtration to provide 4.51g of 3-(2-(1-
benzothiophen-5-yl)ethoxy)propionic acid as white solid
form.
The Chemical shift values of 1H-NMR spectral
in CDCl3 agreed with the values of example 4-1(2).
[0112]
Example 4-4

To toluene(50mL) suspension of 50.0g of 2-(1-
benzothiophen-5-yl)ethanol was added 2.35g of
40%(w/w)benzyltrimethylammonium hydroxide aqueous
solution, and dropwise added 17.9g of acrylonitrile at
8 to 15°C, which was then stirred at 10 to 20°C for 1.5
hours. To this reaction mixture were added 1.25mL of
hydrochloric acid, 100mL of propanol and 5.05g of
water. Thereto was dropwise added 55.0g of sulfuric
acid, which was then refluxed for 6 hours. After
cooling, to the reaction mixture was added 100mL of
water. The organic layer was separated. Thereto was

added 50mL of methanol and dropwise added water(50mL)
solution of 31.5g of potassium hydroxide, which was
then stirred at room temperature for 1.5 hours. To
this reaction mixture were added 75mL of toluene and
75mL of water. The aqueous layer was separated,
thereto was added 100mL of toluene, the pH was adjusted
to 0.9 with 6mol/L hydrochloric acid, and the organic
layer was separated. After the solvent was distilled
off under reduced pressure, thereto were added 50mL of
toluene and 125mL of cyclohexane. The precipitate was
collected by filtration to provide 59.6g of 3-(2-(1-
benzothiophen-5-yl)ethoxy)propionic acid as white solid
form.
The Chemical shift values of 1H-NMR spectral
in CDCl3 agreed with the values of example 4-1(2).
[0113]
Example 4-5

To toluene(260mL) suspension of 260g of 2-(1-
benzothiophen-5-yl)ethanol were added 43.8g of 2-
propanol and 1.64g of potassium tert-butoxide, which
was then stirred for 0.5 hours. After cooling the
reaction mixture to 15°C, thereto was dropwise added
116g of acrylonitrile, which was then stirred at 15 to

25°C for 1 hour. To this reaction mixture were added
6.5mL of hydrochloric acid, 520mL of methanol and 78.9g
of water. Thereto was introduced 310g of hydrogen
chloride at 10 to 25°C, which was then refluxed for 3
hours. After cooling, to the reaction mixture were
added 780mL of water and 520mL of toluene, and the
organic layer was separated. To the organic layer were
dropwise added 260mL of methanol and water(260mL)
solution of 164g of potassium hydroxide, which was then
stirred at 30 to 35°C for 2 hours. To this reaction
mixture was added 260mL of water, and the aqueous layer
was separated. To the aqueous layer were added 520mL
of toluene and 260mL of water and dropwise added 234mL
of hydrochloric acid, and the organic layer was
separated. After 390mL of solvent was distilled off
under reduced pressure from the organic layer, thereto
was added 1040mL of cyclohexane. The precipitate was
collected by filtration to provide 326g of 3-(2-(1-
benzothiophen-5-yl)ethoxy)propionic acid as white solid
form.
The Chemical shift values of 1H-NMR spectral
in CDCl3 agreed with the values of example 4-1(2).
[0114]
Example 4-6
To toluene(360mL) suspension of 180g of 2-(1-
benzothiophen-5-yl)ethanol was added 4.22g of aqueous
solution of 40%(w/w)benzyltrimethylammonium hydroxide,
and dropwise added 8.04g of acrylonitrile at 30°C.

After cooling the reaction mixture to 20°C, thereto was
dropwise added 53.6g of acrylonitrile, which was then
stirred at 15 to 25°C for 2 hours. To this reaction
mixture were added 27mL of hydrochloric acid and 180mL
of methanol. Thereto was introduced 97g of hydrogen
chloride at 10 to 25°C, which was then stirred at 30 to
40°C for 30 minutes and refluxed for 3 hours. After
cooling, to the reaction mixture was added 360mL of
water, and the organic layer was separated. To the
organic layer were dropwise added 180mL of methanol,
and water(180mL) solution of 113g of potassium
hydroxide, which was then stirred at 30 to 35°C for 2
hours. To the reaction mixture was added 360mL of
water, and the aqueous layer was separated. To this
aqueous layer was added 360mL of toluene and dropwise
added 151mL of hydrochloric acid, and the organic layer
was separated. After 126mL of solvent was distilled
off under normal pressure from the organic layer,
thereto was added 1080mL of cyclohexane. The
precipitate was collected by filtration to provide 222g
of 3-(2-(1-benzothiophen-5-yl)ethoxy)propionic acid as
white solid form.
The Chemical shift values of 1H-NMR spectral
in CDCl3 agreed with the values of example 4-1(2).
[0115]
Example 5-1

In 15mL of 1,2-dimethoxyethane was dissolved
10.0g of 3-(2-(1-benzothiophen-5-yl)ethoxy)propionic
acid. Thereto were added 0.lmL of N,N-
dimethylformamide and 5.23g of thionyl chloride, which
was then stirred at room temperature for 1.5 hours.
This reaction solution was dropwise added to a mixed
solution of 50mL of water, 7.19g of sodium hydroxide
and 7.69g of 3-azetidinol 1/2 tartrate at 5 to 15°C,
which was then stirred at same temperature for 2 hours.
Thereto was added 90mL of water. The precipitate was
collected by filtration to provide 11.0g of 1-(3-(2-(1-
benzothiophen-5-yl)ethoxy)propionyl)azetidin-3-ol as
white solid form.
1H-NMR(CDCl3) δ value:
2.25-2.35(2H,m),2.96(2H,t,J=7.0Hz),3.65-3.80
(5H,m),3.85-3.95(lH,m),4.05-4.15(lH,m),4.15-
4.25(lH,m),4.40-4.50(lH,m),7.19(1H,dd,J=8.3,1.5Hz) ,
7.27(lH,d,J=5.4Hz),7.40(1H,d,J=5.4Hz),7.62-7.66(lH,m),
7.78(lH,d,J=8.3Hz)
[0116]
Example 5-2
To 116mL of toluene was suspended 29.0g of 3-

(2-(1-benzothiophen-5-yl)ethoxy)propionic acid.
Thereto were added 0.6mL of N,N-dimethylformamide and
14.5g of thionyl chloride, which was then stirred at
room temperature for 2 hours. After that, 62mL of
solvent was distilled off under reduced pressure. This
reaction solution was dropwise added to a mixed
solution of 87mL of water, 13.9g of sodium hydroxide
and 25.7g of 3-azetidinol 1/2 tartrate at 10 to 20°C,
which was then stirred at 20 to 25°C for 1 hour and left
unattended overnight. After cooling the reaction
solution, the pH was adjusted to 6 with 7mL of acetic
acid. After stirring at 10 to 15°C for 1 hour, the
precipitate was collected by filtration to provide
31.9g of 1-(3-(2-(1-benzothiophen-5-
yl)ethoxy)propionyl)azetidin-3-ol as white solid form.
The Chemical shift values of 1H-NMR spectral
in CDCl3 agreed with the values of example 5-1.
[0117]
Example 5-3
In 75mL of 1,2-dimethoxyethane was dissolved
50.0g of 3-(2-(1-benzothiophen-5-yl)ethoxy)propionic
acid. Thereto was added 26.1g of thionyl chloride,
which was then refluxed for 2 hours. After cooling,
this reaction solution was dropwise added to a mixed
solution of 125mL of water, 20.0g of sodium hydroxide
and 25.2g of 3-azetidinol hydrochloride at -5 to 10°C,
which was then stirred at 0 to 15°C for 30 minutes.
Thereto was added 75mL of water, which was heated to

40°C and dissolved. After cooling, the precipitate was
collected by filtration to provide 56.5g of 1-(3-(2-(1-
benzothiophen-5-yl)ethoxy)propionyl)azetidin-3-ol as
white solid form.
The Chemical shift values of 1H-NMR spectral
in CDCl3 agreed with the values of example 5-1.
[0118]
Example 6-1

To bis(2-methoxyethyl) ether(5mL) suspension
of 1.00g of 1-(3-(2-(1-benzothiophen-5-
yl)ethoxy)propionyl)azetidin-3-ol was added 0.37g of
sodium borohydride, which was then cooled to 10°C.
Thereto was dropwise added 2.4 9mL of
chlorotrimethylsilane at 5 to 10°C for 20 minutes, which
was then stirred at room temperature for 2.5h and at
40°C for 4 hours. After cooling, thereto was dropwise
added 3.27mL of 6.0mol/L hydrochloric acid, which was
then stirred at 70 to 75°C for 30 minutes. To the
reaction mixture were added water and ethyl acetate,
and the pH was adjusted to 10.0 with 2.0mol/L sodium

hydroxide aqueous solution. The organic layer was
separated, washed sequentially with water and saturated
sodium chloride aqueous solution. Thereto were added
anhydrous magnesium sulfate and activated carbon.
After insoluble matter was filtered off, the solvent
was distilled off under reduced pressure. To the
resultant residue was added 0.36g of maleic acid, which
was solidified from a mixed solvent(5mL) of ethyl
acetate:2-propanol(4:1) to provide 0.72g of 1-(3-(2~(1-
benzothiophen-5-yl)ethoxy)propyl)azetidin-3-ol maleate
as colorless crystal form.
1H-NMR(DMSO-d6) δ value:
1.65-1.75(2H,m),2.93(2H,t,J=6.9Hz),3.14(2H,t,J=7.4Hz) ,
3.44(2H,t,J=6.0Hz),3.63(2H,t,J=6.9Hz),3.75-3.85(2H,m),
4.15-4.25(2H,m),4.40-4.50(lH,m),6.06(2H,s),7.26
(1H,dd,J=8.3,1.5Hz),7.41(1H,d,J=5.4Hz),7.73(1H,d, J=5.4H
z),7.7 0-7.7 5(lH,m),7.91(1H,d,J=8.3Hz)
[0119]
Example 6-2
To 1,2-dimethoxyethane(5mL) suspension of
l.OOg of 1-(3-(2-(1-benzothiophen-5-
yl)ethoxy)propionyl)azetidin-3-ol was added 0.37g of
sodium borohydride, which was then cooled to 10°C.
Thereto was dropwise added 2.4 9mL of
chlorotrimethylsilane at 5 to 10°C, which was then
stirred at room temperature for 2.5h and at 40°C for 4
hours. After cooling, thereto was dropwise added
3.27mL of 6.0mol/L hydrochloric acid, which was then

stirred at 70 to 75°C for 30 minutes. To the reaction
mixture were added water and ethyl acetate, and the pH
was adjusted to 10.0 with 2.0mol/L sodium hydroxide
aqueous solution. The organic layer was separated,
washed sequentially with water and saturated sodium
chloride aqueous solution. Thereto were added
anhydrous magnesium sulfate and activated carbon.
After insoluble matter was filtered off, the solvent
was distilled off under reduced pressure. To the
resultant residue was added 0.36g of maleic acid, which
was solidified from a mixed solvent(5mL) of ethyl
acetate:2-propanol(4:1) to provide 0.71g of 1-(3-(2-(1-
benzothiophen-5-yl)ethoxy)propyl)azetidin-3-ol maleate
as colorless crystal form.
The Chemical shift values of 1H-NMR spectral
in DMSO-d6 agreed with the values of example 6-1.
[0120]
Example 6-3
To tetrahydrofuran(5mL) suspension of l.OOg
of 1-(3-(2-(1-benzothiophen-5-
yl)ethoxy)propionyl)azetidin-3-ol was added 0.37g of
sodium borohydride, and dropwise added
tetrahydrofuran(lmL) solution of 0.75mL of
trifluoroacetic acid for 30 minutes, which was then
refluxed for 2 hours. After cooling, thereto was
dropwise added 3.27mL of 6.0mol/L hydrochloric acid,
which was then refluxed for 1.5 hours. To the reaction
mixture were added water and ethyl acetate, and the

aqueous layer was separated. To the aqueous layer was
added ethyl acetate, and the pH was adjusted to 10.0
with 20%(w/w) sodium hydroxide aqueous solution. The
organic layer was separated, washed sequentially with
water and saturated sodium chloride aqueous solution,
and dried over anhydrous magnesium sulfate. After
insoluble matter was filtered off, the solvent was
distilled off under reduced pressure. To the resultant
residue was added 0.36g of maleic acid, which was
solidified from a mixed solvent(5mL) of ethyl
acetate:2-propanol(4:1) to provide 0.62g of 1-(3-(2-(1-
benzothiophen-5-yl)ethoxy)propyl)azetidin-3-ol maleate
as colorless crystal form.
The Chemical shift values of 1H-NMR spectral
in DMSO-d6 agreed with the values of example 6-1.
[0121]
Example 6-4
To tetrahydrofuran(3mL) suspension of 0.50g
of 1-(3-(2-(1-benzothiophen-5-yl)ethoxy)propionyl)
azetidin-3-ol was added 0.19g of sodium borohydride,
which was then heated to 50°C. Thereto was dropwise
added tetrahydrofuran(1mL) solution of 0.46mL of
dimethyl sulfate at 50 to 55°C for 10 minutes, which was
then stirred at same temperature for 2.5 hours. After
cooling, thereto was dropwise added 1.64mL of 6.0mol/L
hydrochloric acid, which was then refluxed for 1.5
hours. To the reaction mixture was added ethyl
acetate, and the pH was adjusted to 10.0 with

20%(w/w)sodium hydroxide aqueous solution. The organic
layer was separated, washed sequentially with water and
saturated sodium chloride aqueous solution, and dried
over anhydrous magnesium sulfate. After insoluble
matter was filtered off, the solvent was distilled off
under reduced pressure. To the resultant residue was
added 0.18g of maleic acid, which was solidified from a
mixed solvent(3.75mL) of ethyl acetate:2-propanol(4:1)
to provide 0.49g of 1-(3-(2-(1-benzothiophen-5-
yl)ethoxy)propyl)azetidin-3-ol maleate as colorless
crystal form.
The Chemical shift values of 1H-NMR spectral
in DMSO-d6 agreed with the values of example 6-1.
[0122]
Example 6-5
To bis(2-methoxyethyl) ether (5mL) suspension
of l.OOg of 1-(3-(2-(1-benzothiophen-5-
yl)ethoxy)propionyl)azetidin-3-ol was added 0.37g of
sodium borohydride, which was then cooled to 10°C.
Thereto was dropwise added 2.46mL of 4.0mol/L hydrogen
chloride/dioxane at 5 to 15°C for 12 minutes, which was
then stirred at same temperature for 30 minutes, at
room temperature for 3 hours and at 35 to 40°C for 6
hours. After cooling, thereto was dropwise added
3.27mL of 6.0mol/L hydrochloric acid, which was then
stirred at 65 to 70°C for 1.5 hours. To the reaction
mixture were added water and ethyl acetate, and the pH
was adjusted to 10.0 with 2.0mol/L sodium hydroxide

aqueous solution. The organic layer was separated,
washed sequentially with water and saturated sodium
chloride aqueous solution. Thereto were added
anhydrous magnesium sulfate and activated carbon.
After insoluble matter was filtered off, the solvent
was distilled off under reduced pressure. To the
resultant residue was added 0.36g of maleic acid, which
was solidified from a mixed solvent(5mL) of ethyl
acetate:2-propanol(4:1) to provide 0.86g of 1-(3-(2-(1-
benzothiophen-5-yl)ethoxy)propyl)azetidin-3-ol maleate
as colorless crystal form.
1H-NMR in DMSO-d6 agreed with the values of
example 6-1.
[0123]
Example 6-6
To 1,2-dimethoxyethane(5mL) suspension of
l.OOg of 1-(3-(2-(1-benzothiophen-5-
yl)ethoxy)propionyl)azetidin-3-ol was added 0.37g of
sodium borohydride, which was then cooled to 10°C.
Thereto was dropwise added 2.46mL of 4.0mol/L hydrogen
chloride/dioxane at 5 to 15°C for 10 minutes, which was
then stirred at same temperature for 1 hour, at room
temperature for 3.5 hours and at 35 to 40°C for 6 hours.
After cooling, thereto was dropwise added 3.27mL of
6.0mol/L hydrochloric acid, which was then stirred at
65 to 70°C for 1.5 hours. To the reaction mixture were
added water and ethyl acetate, and the pH was adjusted
to 10.0 with 2.0mol/L sodium hydroxide aqueous

solution. The organic layer was separated, washed
sequentially with water and saturated sodium chloride
aqueous solution. Thereto were added anhydrous
magnesium sulfate and activated carbon. After
insoluble matter was filtered off, the solvent was
distilled off under reduced pressure. To the resultant
residue was added 0.36g of maleic acid, which was
solidified from a mixed solvent(5mL) of ethyl
acetate:2-propanol(4:1) to provide 0.93g of 1-(3-(2-(1-
benzothiophen-5-yl)ethoxy)propyl)azetidin-3-ol maleate
as colorless crystal form.
1H-NMR in DMSO-d6 agreed with the values of example 6-1.
[0124]
Example 6-7
To 1,2-dimethoxyethane(70mL) suspension of
20.0g of 1-(3-(2-(1-benzothiophen-5-
yl)ethoxy)propionyl)azetidin-3-ol was added 5.46g of
sodium borohydride, which was then cooled to 15°C.
Thereto was dropwise added 20.6mL of 7.0mol/L hydrogen
chloride/1,2-dimethoxyethane at 15 to 20°C for 40
minutes, which was then stirred at room temperature for
1.5 hours and at 53 to 57°C for 4 hours. After cooling,
thereto was dropwise added 65.5mL of 6.0mol/L
hydrochloric acid, which was then stirred at 65 to 70°C
for 1 hour. The reaction mixture was concentrated
under reduced pressure, thereto were added 100mL of
water and 100mL of ethyl acetate, and the pH was
adjusted to 10.0 with 5.0mol/L sodium hydroxide aqueous

solution. After the organic layer was separated,
washed with 50mL of water, and the pH was adjusted to
1.0 with 6.0mol/L hydrochloric acid. The aqueous layer
was separated, to which was added 50mL of ethyl
acetate. The pH was adjusted to 10.0 with 5.0mol/L
sodium hydroxide aqueous solution. The organic layer
was separated, to which was added anhydrous magnesium
sulfate. After insoluble matter was filtered off, the
solvent was distilled off under reduced pressure. To
the resultant residue was added 7.22g of maleic acid,
which was solidified from a mixed solvent(100mL) of
ethyl acetate:2-propanol(4:1) to provide 19.2g of 1-(3-
(2-(1-benzothiophen-5-yl)ethoxy)propyl)azetidin-3-ol
maleate as colorless crystal form.
[0125]
Example 6-8
To tetrahydrofuran(35.0mL) suspension of
5.00g of 1-(3-(2-(1-benzothiophen-5-
yl)ethoxy)propionyl)azetidin-3-ol was added 1.61g of
sodium borohydride, and dropwise added
tetrahydrofuran(15mL) solution of 2.09g of sulfuric
acid at room temperature for 30 minutes, which was then
stirred at 48 to 52°C for 7.5 hours. After cooling,
thereto was dropwise added 16.4mL of 6.0mol/L
hydrochloric acid, which was then refluxed for 1 hour.
The reaction mixture was concentrated under reduced
pressure, thereto were added water and ethyl acetate,
and the pH was adjusted to 9.5 with 5.0mol/L sodium

hydroxide aqueous solution. The organic layer was
separated, and washed with saturated sodium chloride
aqueous solution. Thereto were added anhydrous
magnesium sulfate and activated carbon. After
insoluble matter was filtered off, the solvent was
distilled off under reduced pressure. To the resultant
residue was added 1.81g of maleic acid, which was
solidified from a mixed solvent(25mL) of ethyl
acetate:2-propanol(4:1) to provide 4.82g of 1-(3-(2-(1-
benzothiophen-5-yl)ethoxy)propyl)azetidin-3-ol maleate
as colorless crystal form.
1H-NMR in DMSO-d6 agreed with the values of
example 6-1.
[0126]
Example 6-9
To tetrahydrofuran(2.38L) suspension of 340g
of 1-(3-(2-(1-benzothiophen-5-
yl)ethoxy)propionyl)azetidin-3-ol was added 110g of
sodium borohydride, and dropwise added
tetrahydrofuran(1.02L) solution of 142g of sulfuric
acid at room temperature for 1 hour, which was then
stirred at 45 to 55°C for 5 hours. After cooling,
thereto was added 170mL of acetone and dropwise added
204mL of 36% hydrochloric acid, which was then stirred
at room temperature for 3 hours and left unattended
overnight. To the reaction mixture was added 1.02L of
water, and 3.34L of the solvent was distilled off under
reduced pressure. After cooling, thereto was added

0.68L of ethyl acetate, and dropwise added water(0.68L)
solution of 147g of sodium hydroxide at 14 to 22°C,
which was then stirred at 7 to 15°C for 30 minutes.
Insoluble matter was filtered off, washed with 0.34L of
ethyl acetate. The filtrate and washings were
combined, and the organic layer was separated, washed
with 0.68L of water. After to the organic layer was
added 2.04L of 2-propanol, 3.01L of the solvent was
distilled off under reduced pressure. Thereto were
added 1.02L of ethyl acetate and 34g of activated
carbon, which was stirred for 20 minutes. Insoluble
matter was filtered off and washed with 0.34L of ethyl
acetate. The filtrate and washings were combined,
thereto was added 116g of maleic acid. After this
reaction mixture was heated and dissolved, it was
slowly cooled. The precipitate was collected by
filtration to provide 376g of 1-(3-(2-(1-benzothiophen-
5-yl)ethoxy)propyl)azetidin-3-ol maleate as colorless
crystal form.
1H-NMR in DMSO-d6 agreed with the values of
example 6-1.
[0127]
Example 6-10
To tetrahydrofuran(250mL) suspension of 50.0g
of 1-(3-(2-(1-benzothiophen-5-
yl)ethoxy)propionyl)azetidin-3-ol was added 13.6g of
sodium borohydride, and dropwise added 18.5g of
sulfuric acid at room temperature for 3 hours, which

was then stirred at 45 to 55°C for 4.5 hours. After
cooling, thereto was added 15mL of acetone and dropwise
added 120mL of 6.0mol/L hydrochloric acid, which was
then refluxed for 1 hour. To the reaction mixture was
added 150mL of water, and the solvent was distilled off
under reduced pressure. Thereto was added 200mL of
ethyl acetate, and dropwise added water(100mL) solution
of 43.9g of sodium hydroxide at 10 to 21°C. The organic
layer was separated, washed with 20% sodium chloride
aqueous solution. Thereto were added 50.0g of zeolite
and 5.0g of activated carbon, which was then stirred
for 20 minutes. Insoluble matter was filtered off and
washed with lOOmL of ethyl acetate. The filtrate and
washings were combined, thereto were added 63mL of
ethyl acetate, 75mL of 2-propanol and 17.1g of maleic
acid. After this reaction mixture was heated and
dissolved, it was slowly cooled. The precipitate was
collected by filtration to provide 56.7g of 1-(3-(2-(1-
benzothiophen-5-yl)ethoxy)propyl)azetidin-3-ol maleate
as colorless crystal form.
1H-NMR in DMSO-d6 agreed with the values of example 6-1.
INDUSTRIAL APPLICABILITY
[0128]
The process for production of 1-(3-(2-(1-
benzothiophen-5-yl)ethoxy)propyl)azetidin-3-ol and
salts thereof of the present invention has the
following characteristics, (1) safety to human body,

(2) low environmental loads and (3) a possibility of
mass production, and so forth, therefore, the process
of 1-(3-(2-(1-benzothiophen-5-
yl)ethoxy)propyl)azetidin-3-ol and salts thereof is
useful as industrial manufacturing process.

WE CLAIM:
1. A process for production of 3-(2-(1-benzothiophen-5-yl)
ethoxy)propionic acid or salts thereof characterized by subjecting
2-(1-benzothiophen-5-yl)ethanol to Michael addition reaction with
acrylonitrile in the presence of base, subsequently subjecting it to
reaction with an alcohol represented by the general formula:
R1CH2OH
wherein R1 represents a hydrogen atom or an unsubstituted or
substituted alkyl, cycloalkyl or aryl group,
in the presence of acid to obtain a propionic acid ester derivative
represented by the general formula:

wherein R1 has the same meanings as the above,
subsequently subjecting the propionic acid ester derivative to
hydrolysis reaction in the presence of base.
2. The process for production of 3-(2-(1-benzothiophen-5-yl)
ethoxy)propionic acid or salts thereof wherein by subjecting 2-(1-
benzothiophen-5-yl)ethanol to Michael addition reaction with
acrylonitrile in the presence of base, subsequently subjecting it to
reaction with an alcohol represented by the general formula:
R1CH2OH
wherein R1 represents a hydrogen atom or an unsubstituted or
substituted alkyl, cycloalkyl or aryl group,

in the presence of acid to obtain a propionic acid ester derivative
represented by the general formula:

wherein R1 has the same meanings as the above, and subjecting the
propionic acid ester derivative to hydrolysis reaction in the presence
of base as claimed in claim 1, wherein the acid used is sulfuric acid or
hydrogen chloride.

3. The process for production of 3- (2- (1-benzothiophen-5-yl)
ethoxy)propionic acid or salts thereof wherein by subjecting 2- (1-
benzothiophen-5-yl)ethanol to Michael addition reaction with
acrylonitrile in the presence of base, subsequently subjecting it to
reaction with an alcohol represented by the general formula:
R1CH2OH
wherein R1 represents a hydrogen atom or an unsubstituted or
substituted alkyl, cycloalkyl or aryl group,
in the presence of acid to obtain a propionic acid ester derivative
represented by the general formula:

wherein R1 has the same meanings as the above, and subjecting the
propionic acid ester derivative to hydrolysis reaction in the presence
of base as claimed in claim 1 or 2, wherein the acid used is hydrogen
chloride and R1 is a hydrogen atom.
4. The process for production of 3-(2-(1-benzothiophen-5-yl)
ethoxy)propionic acid or salts thereof wherein by subjecting 2-(1-
benzothiophen-5-yl) ethanol to Michael addition reaction with
acrylonitrile in the presence of base, subsequently subjecting it to
reaction with an alcohol represented by the general formula:
R1CH2OH

wherein R1 represents a hydrogen atom or an unsubstituted or
substituted alkyl, cycloalkyl or aryl group,
in the presence of acid to obtain a propionic acid ester derivative
represented by the general formula:

wherein R1 has the same meanings as the above,
and subjecting the propionic acid ester derivative to hydrolysis
reaction in the presence of base as claimed in claim 1 or 2, wherein
the acid used is sulfuric acid and R1 is ethyl group.

ABSTRACT

Title: Process for production of 1-(3-(2-(1-Benzothiophen-5-yl)-
ethoxy)propyl)azetidin-3-ol or salts thereof
A process for production of 3-(2-(1-benzothiophen-5-yl)
ethoxy)propionic acid or salts thereof characterized by subjecting 2-
(1-benzothiophen-5-yl)ethanol to Michael addition reaction with
acrylonitrile in the presence of base, subsequently subjecting it to
reaction with an alcohol represented by the general formula:
R1CH2OH
wherein R1 represents a hydrogen atom or an unsubstituted or
substituted alkyl, cycloalkyl or aryl group,
in the presence of acid to obtain a propionic acid ester derivative
represented by the general formula:

wherein R1 has the same meanings as the above,
subsequently subjecting the propionic acid ester derivative to
hydrolysis reaction in the presence of base.